6-membered heteroaromatic substituted cyanoindoline derivatives as NIK inhibitors

ABSTRACT

The present invention relates to pharmaceutical agents of formula (I), useful for therapy and/or prophylaxis in a mammal, and in particular to inhibitors of NF-κB-inducing kinase (NIK—also known as MAP3K14) useful for treating diseases such as cancer, inflammatory disorders, metabolic disorders and autoimmune disorders. The invention is also directed to pharmaceutical compositions comprising such compounds, and to the use of such compounds or pharmaceutical compositions for the prevention or treatment of diseases such as a cancer, inflammatory disorders, metabolic disorders including obesity and diabetes, and autoimmune disorders.

FIELD OF THE INVENTION

The present invention relates to pharmaceutical agents useful for therapy and/or prophylaxis in a mammal, and in particular to inhibitors of NF-κB-inducing kinase (NIK—also known as MAP3K14) useful for treating diseases such as cancer (in particular B-cell malignancies including leukemias, lymphomas and myeloma), inflammatory disorders, metabolic disorders including obesity and diabetes, and autoimmune disorders. The invention is also directed to pharmaceutical compositions comprising such compounds, and to the use of such compounds or pharmaceutical compositions for the prevention or treatment of diseases such as cancer, inflammatory disorders, metabolic disorders including obesity and diabetes, and autoimmune disorders.

BACKGROUND OF THE INVENTION

The present invention relates to pharmaceutical agents useful for therapy and/or prophylaxis in a mammal, and in particular to inhibitors of NF-κB-inducing kinase (NIK—also known as MAP3K14) useful for treating diseases such as cancer and inflammatory disorders. Nuclear factor-kappa B (NF-κB) is a transcription factor regulating the expression of various genes involved in the immune response, cell proliferation, adhesion, apoptosis, and carcinogenesis. NF-κB dependent transcriptional activation is a tightly controlled signaling pathway, through sequential events including phosphorylation and protein degradation. NIK is a serine/threonine kinase which regulates NF-κB pathway activation. There are two NF-κB signaling pathways, the canonical and the non-canonical. NIK is indispensable for the non-canonical signaling pathway where it phosphorylates IKKα, leading to the partial proteolysis of p100; liberating p52 which then heterodimerizes with RelB, translocates to the nucleus and mediates gene expression. The non-canonical pathway is activated by only a handful of ligands such as CD40 ligands, B-cell activating factor (BAFF), lymphotoxin β receptor ligands and TNF-related weak inducer of apoptosis (TWEAK) and NIK has been shown to be required for activation of the pathway by these ligands. Because of its key role, NIK expression is tightly regulated. Under normal non-stimulated conditions NIK protein levels are very low, this is due to its interaction with a range of TNF receptor associated factors (TRAF2 and TRAF3), which are ubiquitin ligases and result in degradation of NIK. It is believed that when the non-canonical pathway is stimulated by ligands, the activated receptors now compete for TRAFs, dissociating the TRAF-NIK complexes and thereby increasing the levels of NIK. (Thu and Richmond, Cytokine Growth F. R. 2010, 21, 213-226)

Research has shown that blocking the NF-κB signaling pathway in cancer cells can cause cells to stop proliferating, to die and to become more sensitive to the action of other anti-cancer therapies. A role for NIK has been shown in the pathogenesis of both hematological malignancies and solid tumours.

The NF-κB pathway is dysregulated in multiple myeloma due to a range of diverse genetic abnormalities that lead to the engagement of the canonical and non-canonical pathways (Annuziata et al. Cancer Cell 2007, 12, 115-130; Keats et al. Cancer Cell 2007, 12, 131-144; Demchenko et al. Blood 2010, 115, 3541-3552). Myeloma patient samples frequently have increased levels of NIK activity. This can be due to chromosomal amplification, translocations (that result in NIK proteins that have lost TRAF binding domains), mutations (in the TRAF binding domain of NIK) or TRAF loss of function mutations. Researchers have shown that myeloma cell lines can be dependent on NIK for proliferation; in these cell lines if NIK activity is reduced by either shRNA or compound inhibition, this leads to a failure in NF-κB signaling and the induction of cell death (Annuziata 2007).

In a similar manner, mutations in TRAF and increased levels of NIK have also been seen in samples from Hodgkin lymphoma (HL) patients. Once again proliferation of cell lines derived from HL patients is susceptible to inhibition of NIK function by both shRNA and compounds (Ranuncolo et al. Blood First Edition Paper, 2012, DOI 10.1182/blood-2012-01-405951).

NIK levels are also enhanced in adult T cell leukemia (ATL) cells and targeting NIK with shRNA reduced ATL growth in vivo (Saitoh et al. Blood 2008, 111, 5118-5129). It has been demonstrated that the API2-MALT1 fusion oncoprotein created by the recurrent translocation t(11; 18)(q21; q21) in mucosa-associated lymphoid tissue (MALT) lymphoma induces proteolytic cleavage of NF-κB-inducing kinase (NIK) at arginine 325. NIK cleavage generates a C-terminal NIK fragment that retains kinase activity and is resistant to proteasomal degradation (due to loss of TRAF binding region). The presence of this truncated NIK leads to constitutive non-canonical NF-κB signaling, enhanced B cell adhesion, and apoptosis resistance. Thus NIK inhibitors could represent a new treatment approach for refractory t(11; 18)-positive MALT lymphoma (Rosebeck et al. Science 2011, 331, 468-472).

NIK aberrantly accumulates in diffuse large B-cell lymphoma (DLBCL) cells due to constitutive activation of B-cell activation factor (BAFF) through interaction with autochthonous B-lymphocyte stimulator (BLyS) ligand. NIK accumulation in human DLBCL cell lines and patient tumor samples suggested that constitutive NIK kinase activation is likely to be a key signaling mechanism involved in abnormal lymphoma tumor cell proliferation. Growth assays showed that using shRNA to inhibit NIK kinase protein expression in GCB- and ABC-like DLBCL cells decreased lymphoma cell growth in vitro, implicating NIK-induced NF-κB pathway activation as having a significant role in DLBCL proliferation (Pham et al. Blood 2011, 117, 200-210). More recently, also loss-of-function mutations in TRAF3 have been characterized in human and canine DLBCL (Bushell et al., Blood 2015, 125, 999-1005).

Recently, similar mutations in the non-cannonical NFkB signaling pathway (TRAF2, TRAF3, NIK, BIRC3) were found in ibrutinib-refractory mantle cell lymphoma cell lines (Rahal et al., Nat Med 2014, 1, 87-92).

As mentioned a role of NIK in tumour cell proliferation is not restricted to hematological cells, there are reports that NIK protein levels are stabilised in some pancreatic cancer cell lines and as seen in blood cells proliferation of these pancreatic cancer lines are susceptible to NIK siRNA treatment (Nishina et al. Biochem. Bioph. Res. Co. 2009, 388, 96-101). Constitutive activation of NF-κB, is preferentially involved in the proliferation of basal-like subtype breast cancer cell lines, including elevated NIK protein levels in specific lines (Yamamoto et al. Cancer Sci. 2010, 101, 2391-2397). In melanoma tumours, tissue microarray analysis of NIK expression revealed that there was a statistically significant elevation in NIK expression when compared with benign tissue. Moreover, shRNA techniques were used to knock-down NIK, the resultant NIK-depleted melanoma cell lines exhibited decreased proliferation, increased apoptosis, delayed cell cycle progression and reduced tumor growth in a mouse xenograft model (Thu et al. Oncogene 2012, 31(20), 2580-92). A wealth of evidence showed that NF-κB is often constitutively activated in non-small cell lung cancer tissue specimens and cell lines. Depletion of NIK by RNAi induced apoptosis and affected efficiency of anchorage-independent NSCLC cell growth.

In addition research has shown that NF-κB controls the expression of many genes involved in inflammation and that NF-κB signalling is found to be chronically active in many inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease, sepsis and others. Thus pharmaceutical agents capable of inhibiting NIK and thereby reducing NF-κB signaling pathway can have a therapeutic benefit for the treatment of diseases and disorders for which over-activation of NF-κB signaling is observed.

Dysregulated NF-κB activity is associated with colonic inflammation and cancer, and it has been shown that Nlrp12 deficient mice were highly susceptible to colitis and colitis-associated colon cancer. In this context work showed that NLRP12 functions as a negative regulator of the NF-κB pathway through its interaction and regulation of NIK and TRAF3, and as a checkpoint of critical pathways associated with inflammation and inflammation-associated tumorigenesis (Allen et al. Immunity 2012, 36, 742-754).

Tumor necrosis factor (TNF)-α, is secreted in response to inflammatory stimuli in diseases such as rheumatoid arthritis and inflammatory bowel disease. In a series of experiments in colonic epithelial cells and mouse embryonic fibroblasts, TNF-α mediates both apoptosis and inflammation, stimulating an inflammatory cascade through the non-canonical pathway of NF-κB activation, leading to increased nuclear RelB and p52. TNF-α induced the ubiquitination of TRAFs, which interacts with NIK, leading to increased levels of phospho-NIK (Bhattacharyya et al. J Biol. Chem. 2011, 285, 39511-39522).

Inflammatory responses are a key component of chronic obstructive pulmonary disease (COPD) as such it has been shown that NIK plays a key role in exacerbating the disease following infection with the Gram-negative bacterium nontypeable Hemophilus influenza (Shuto et al. PNAS 2001, 98, 8774-8779). Likewise cigarette smoke (CS) contains numerous reactive oxygen/nitrogen species, reactive aldehydes, and quinones, which are considered to be some of the most important causes of the pathogenesis of chronic inflammatory lung diseases, such as COPD and lung cancer. Increased levels of NIK and p-IKKα have been observed in peripheral lungs of smokers and patients with COPD. In addition it has been shown that endogenous NIK is recruited to promoter sites of pro-inflammatory genes to induce post-translational modification of histones, thereby modifying gene expression profiles, in response to CS or TNFα (Chung et al. PLoS ONE 2011, 6(8): e23488. doi:10.1371/joumal.pone.0023488). A shRNA screen was used in an in vitro model of oxidative stress induced cell death (as a model of COPD) to interrogate a human druggable genome siRNA library in order to identify genes that modulate the cellular response to stress. NIK was one of the genes identified in this screen as a potential new therapeutic target to modulate epithelial apoptosis in chronic lung diseases (Wixted et al. Toxicol. In Vitro 2010, 24, 310-318).

Diabetic individuals can be troubled by a range of additional manifestations associated with inflammation. One such complication is cardiovascular disease and it has been shown that there are elevated levels of p-NIK, p-IKK-α/β and p-IκB-α in diabetic aortic tissues (Bitar et al. Life Sci. 2010, 86, 844-853). In a similar manner, NIK has been shown to regulate proinflammatory responses of renal proximal tubular epithelial cells via mechanisms involving TRAF3. This suggests a role for NF-κB noncanonical pathway activation in modulating diabetes-induced inflammation in renal tubular epithelium (Zhao et al. Exp. Diabetes Res. 2011, 1-9). The same group has shown that NIK plays a critical role in noncanonical NF-κB pathway activation, induced skeletal muscle insulin resistance in vitro, suggesting that NIK could be an important therapeutic target for the treatment of insulin resistance associated with inflammation in obesity and type 2 diabetes (Choudhary et al. Endocrinology 2011, 152, 3622-3627).

NF-κB is an important component of both autoimmunity and bone destruction in rheumatoid arthritis (RA). Mice lacking functional NIK have no peripheral lymph nodes, defective B and T cells, and impaired receptor activator of NF-κB ligand-stimulated osteoclastogenesis. Aya et al. (J. Clin. Invest. 2005, 115, 1848-1854) investigated the role of NIK in murine models of inflammatory arthritis using Nik−/− mice. The serum transfer arthritis model was initiated by preformed antibodies and required only intact neutrophil and complement systems in recipients. While Nik−/− mice had inflammation equivalent to that of Nik+/+ controls, they showed significantly less periarticular osteoclastogenesis and less bone erosion. In contrast, Nik−/− mice were completely resistant to antigen-induced arthritis (AIA), which requires intact antigen presentation and lymphocyte function but not lymph nodes. Additionally, transfer of Nik+/+ splenocytes or T cells to Rag2−/− mice conferred susceptibility to AIA, while transfer of Nik−/− cells did not. Nik−/− mice were also resistant to a genetic, spontaneous form of arthritis, generated in mice expressing both the KRN T cell receptor and H-2 g7. The same group used transgenic mice with OC-lineage expression of NIK lacking its TRAF3 binding domain (NT3), to demonstrate that constitutive activation of NIK drives enhanced osteoclastogenesis and bone resorption, both in basal conditions and in response to inflammatory stimuli (Yang et al. PLoS ONE 2010, 5(11): e15383. doi:10.1371/joumal.pone.0015383). Thus this group concluded that NIK is important in the immune and bone-destructive components of inflammatory arthritis and represents a possible therapeutic target for these diseases.

It has also been hypothesized that manipulating levels of NIK in T cells may have therapeutic value. Decreasing NIK activity in T cells might significantly ameliorate autoimmune responses and alloresponses, like GVHD (Graft Versus Host Disease) and transplant rejection, without crippling the immune system as severely as do inhibitors of canonical NF-κB activation.

WO2003030909 describes the preparation of 2- and 4-aminopyrimidines N-substituted by a bicyclic ring for use as kinase inhibitors in the treatment of cancer.

WO2002079197 describes 4-aryl-substituted 2-pyrimidinamines and 2-pyridinamines, useful as inhibitors of c-Jun N-terminal kinases (JNK) and other protein kinases.

DESCRIPTION OF THE INVENTION

The present invention concerns novel compounds of Formula (I):

tautomers and stereoisomeric forms thereof, wherein R¹ represents C₁₋₄alkyl; R² represents C₁₋₆alkyl, or C₁₋₆alkyl substituted with one R⁵; Y represents CR⁴ or N; R⁴ represents hydrogen or halo; R⁵ represents halo, Het^(3a), —NR^(6a)R^(6b), or —OR⁷; R^(6a) represents hydrogen or C₁₋₄alkyl; R^(6b) represents hydrogen; C₁₋₄alkyl; C₃₋₆cycloalkyl; —C(═O)—C₁₋₄alkyl; —C(═O)—Het⁴; —S(═O)₂—C₁₋₄alkyl; —C(═O)—C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —NR^(16a)R^(16b); or C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —S(═O)₂—C₁₋₄alkyl; R⁷ represents hydrogen, C₁₋₄alkyl, —C₁₋₄alkyl-NR^(8a)R^(8b), —C(═O)—R⁹, —S(═O)₂—OH, —P(═O)₂—OH, —(C═O)—CH(NH₂)—C₁₋₄alkyl-Ar¹, or —C₁₋₄alkyl-Het^(3b); R^(8a) represents hydrogen or C₁₋₄alkyl; R^(8b) represents hydrogen, C₁₋₄alkyl, or C₃₋₆cycloalkyl; R⁹ represents C₁₋₆alkyl, or C₁₋₆alkyl substituted with one substituent selected from the group consisting of —NH₂, —COOH, and Het⁶; R^(16a) and R^(16b) each independently represents hydrogen, C₁₋₄alkyl or C₃₋₆cycloalkyl; R³ represents a 6-membered heteroaromatic ring containing 1 or 2 N-atoms, optionally substituted with one, two or three substituents each independently selected from the group consisting of halo; cyano; C₁₋₆alkyl; —O—C₁₋₄alkyl; —C(═O)—R¹⁰; —S(═O)₂—C₁₋₄alkyl; —S(═O)(═N—R^(20a))—C₁₋₄alkyl; —O—C₁₋₄alkyl substituted with one, two or three halo atoms; —O—C₁₋₄alkyl-R¹²; C₃₋₆cycloalkyl; —O—C₃₋₆cycloalkyl; Het^(1a); —O-Het^(1b); R¹⁸; R²¹; —P(═O)—(C₁₋₄alkyl)₂; —NH—C(═O)—C₁₋₄alkyl; —NH—C(═O)—Het^(1g); —NR^(17a)R^(17b); C₁₋₄alkyl substituted with one, two or three halo atoms; C₁₋₄alkyl substituted with one, two or three —OH substituents; C₁₋₄alkyl substituted with one R¹³; C₁₋₄alkyl substituted with one R¹⁸; C₂₋₆alkenyl; C₂₋₆alkenyl substituted with one R¹³; C₂₋₆alkynyl; and C₂₋₆alkynyl substituted with one R¹³; or R³ represents 2-oxo-1,2-dihydropyridin-3-yl, wherein said 2-oxo-1,2-dihydropyridin-3-yl may optionally be substituted on the N-atom with a substituent selected from the group consisting of C₁₋₆alkyl; C₃₋₆cycloalkyl; Het^(1a); R¹⁸; R²¹; C₁₋₄alkyl substituted with one, two or three halo atoms; C₁₋₄alkyl substituted with one, two or three —OH substituents; C₁₋₄alkyl substituted with one R¹³; C₁₋₄alkyl substituted with one R¹⁸; C₂₋₆alkenyl; and C₂₋₆alkenyl substituted with one R¹³; provided that when Het^(1a) or R¹⁸ are directly attached to the N-atom of the 2-oxo-1,2-dihydropyridin-3-yl, said Het^(1a) or R¹⁸ are attached to the N-atom via a ring carbon atom; and wherein said 2-oxo-1,2-dihydropyridin-3-yl may optionally be substituted on the ring carbon atoms with in total one, two or three substituents each independently selected from the group consisting of halo; cyano; C₁₋₆alkyl; —O—C₁₋₄alkyl; —C(═O)—R¹⁰; —S(═O)₂—C₁₋₄alkyl; —S(═O)(═N—R^(20a))—C₁₋₄alkyl; —O—C₁₋₄alkyl substituted with one, two or three halo atoms; —O—C₁₋₄alkyl-R¹²; C₃₋₆cycloalkyl; —O—C₃₋₆cycloalkyl; Het^(1a); —O-Het^(1b); R¹⁸; R²¹; —P(═O)—(C₁₋₄alkyl)₂; —NH—C(═O)—C₁₋₄alkyl; —NH—C(═O)—Het^(1a); —NR^(17a)R^(17b); C₁₋₄alkyl substituted with one, two or three halo atoms; C₁₋₄alkyl substituted with one, two or three —OH substituents; C₁₋₄alkyl substituted with one R¹³; C₁₋₄alkyl substituted with one R¹⁸; C₂₋₆alkenyl; C₂₋₆alkenyl substituted with one R¹³; C₂₋₆alkynyl; and C₂₋₆alkynyl substituted with one R¹³; R¹⁰ represents —OH, —O—C₁₋₄alkyl, —NR^(11a)R^(11b) or Het²; R¹⁸ represents a 5-membered aromatic ring containing one, two or three N-atoms; wherein said 5-membered aromatic ring may optionally be substituted with one substituent selected from the group consisting of C₁₋₄alkyl and C₃₋₆cycloalkyl; R²¹ represents 3,6-dihydro-2H-pyran-4-yl or 1,2,3,6-tetrahydro-4-pyridinyl, wherein 1,2,3,6-tetrahydro-4-pyridinyl may optionally be substituted on the N-atom with C₁₋₄alkyl or C₃₋₆cycloalkyl; Het^(1a), Het^(1c) and Het^(1d) each independently represents a 4- to 7-membered monocyclic saturated heterocyclyl containing one or two heteroatoms each independently selected from O, S, S(═O)_(p) and N; or a 6- to 11-membered bicyclic saturated heterocyclyl, including fused, spiro and bridged cycles, containing one, two or three heteroatoms each independently selected from O, S, S(═O)_(p) and N; wherein said 4- to 7-membered monocyclic saturated heterocyclyl or said 6- to 11-membered bicyclic saturated heterocyclyl may optionally be substituted, where possible, on one, two or three ring N-atoms with a substituent each independently selected from the group consisting of C₁₋₄alkyl, C₃₋₆cycloalkyl, and C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —O—C₁₋₄alkyl; and wherein said 4- to 7-membered monocyclic saturated heterocyclyl or said 6- to 11-membered bicyclic saturated heterocyclyl may optionally be substituted on one, two or three ring C-atoms with one or two substituents each independently selected from the group consisting of —OH, halo, C₁₋₄alkyl, cyano, —C(═O)—C₁₋₄alkyl, —O—C₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)₂; Het^(1b), Het^(1e), Het^(1g), Het⁴, Het⁷ and Het⁸ each independently represents a 4- to 7-membered monocyclic saturated heterocyclyl, attached to the remainder of the molecule of Formula (I) through any available ring carbon atom, said Het^(1b), Het^(1e), Het^(1g), Het⁴, Het⁷ and Het⁸ containing one or two heteroatoms each independently selected from O, S, S(═O)_(p) and N; wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted, where possible, on one or two ring N-atoms with a substituent each independently selected from the group consisting of C₁₋₄alkyl, C₃₋₆cycloalkyl, and C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —O—C₁₋₄alkyl; and wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted on one, two or three ring C-atoms with one or two substituents each independently selected from the group consisting of —OH, halo, C₁₋₄alkyl, cyano, —C(═O)—C₁₋₄alkyl, —O—C₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)₂; Het² represents a heterocyclyl of formula (b-1):

(b-1) represents a N-linked 4- to 7-membered monocyclic saturated heterocyclyl optionally containing one additional heteroatom selected from O, S, S(═O)_(p) and N, or a N-linked 6- to 11-membered bicyclic saturated heterocyclyl, including fused, spiro and bridged cycles, optionally containing one or two additional heteroatoms each independently selected from O, S, S(═O)_(p) and N; wherein in case (b-1) contains one or two additional N-atoms, said one or two N-atoms may optionally be substituted with a substituent each independently selected from the group consisting of C₁₋₄alkyl, C₃₋₆cycloalkyl and Het⁷; and wherein (b-1) may optionally be substituted on one, two or three ring C-atoms with one or two substituents each independently selected from the group consisting of halo, —OH, cyano, C₁₋₄alkyl, —O—C₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, and C₁₋₄alkyl-OH; R^(11b) represents hydrogen; Het^(1e); C₁₋₄alkyl; —C₁₋₄alkyl-Het⁵; —C₁₋₄alkyl-Het⁸; C₁₋₄alkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, —OH and —O—C₁₋₄alkyl; C₃₋₆cycloalkyl; or C₃₋₆cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, —OH and —O—C₁₋₄alkyl; R¹³ represents —O—C₁₋₄alkyl, —C(═O)NR^(15a)R^(15b), —NR^(19a)R^(19b), C₃₋₆cycloalkyl, Het^(1d), or —C(═O)—Het^(1f); R¹² represents —OH, —O—C₁₋₄alkyl, —NR^(14a)R^(14b), —C(═O)NR^(14c)R^(14d), —S(═O)₂—C₁₋₄alkyl, —S(═O)(═N—R^(20b))—C₁₋₄alkyl, C₃₋₆cycloalkyl, Ar², or Het^(1c); Ar¹ represents phenyl optionally substituted with one hydroxy; Ar² represents phenyl optionally substituted with one C₁₋₄alkyl; Het^(3a), Het^(3b), Het⁵, Het⁶ and Het^(1f) each independently represents a heterocyclyl of formula (c-1):

(c-1) represents a N-linked 4- to 7-membered monocyclic saturated heterocyclyl optionally containing one additional heteroatom selected from O, S, S(═O)_(p) and N; wherein in case (c-1) contains one additional N-atom, said additional N-atom may optionally be substituted with C₁₋₄alkyl or C₃₋₆cycloalkyl; and wherein (c-1) may optionally be substituted on one or two ring C-atoms atoms with one or two substituents each independently selected from the group consisting of halo, C₁₋₄alkyl, and C₃₋₆cycloalkyl; R^(11a), R^(14n), R^(14c), R^(15a), R^(17a) and R^(19a) each independently represents hydrogen or C₁₋₄alkyl; R^(14b), R^(14d), R^(15b), R^(17b) and R^(19b) each independently represents hydrogen; C₁₋₄alkyl; C₃₋₆cycloalkyl; —C(═O)—C₁₋₄alkyl; C₁₋₄alkyl substituted with one substituent selected from the group consisting of halo, —OH and —O—C₁₋₄alkyl; —C(═O)—C₁₋₄alkyl substituted with one substituent selected from the group consisting of halo, —OH and —O—C₁₋₄alkyl; or —S(═O)₂—C₁₋₄alkyl; R^(20a) and R^(20b) each independently represents hydrogen; C₁₋₄alkyl; C₃₋₆cycloalkyl; or C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —O—C₁₋₄alkyl; p represents 1 or 2; and the pharmaceutically acceptable addition salts, and the solvates thereof.

The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I), a pharmaceutically acceptable addition salt, or a solvate thereof, and a pharmaceutically acceptable carrier or excipient.

Additionally, the invention relates to a compound of Formula (I), a pharmaceutically acceptable addition salt, or a solvate thereof, for use as a medicament, and to a compound of Formula (I), a pharmaceutically acceptable addition salt, or a solvate thereof, for use in the treatment or in the prevention of cancer, inflammatory disorders, autoimmune disorders, and metabolic disorders such as diabetes and obesity.

In a particular embodiment, the invention relates to a compound of Formula (I), a pharmaceutically acceptable addition salt, or a solvate thereof, for use in the treatment or in the prevention of a haematological malignancy or solid tumour.

In a specific embodiment said haematological malignancy is selected from the group consisting of multiple myeloma, Hodgkin lymphoma, T-cell leukaemia, mucosa-associated lymphoid tissue lymphoma, diffuse large B-cell lymphoma and mantle cell lymphoma. In another specific embodiment of the present invention, the solid tumour is selected from the group consisting of pancreatic cancer, breast cancer, melanoma and non-small cell lung cancer.

The invention also relates to the use of a compound of Formula (I), a pharmaceutically acceptable addition salt, or a solvate thereof, in combination with an additional pharmaceutical agent for use in the treatment or prevention of cancer, inflammatory disorders, autoimmune disorders, and metabolic disorders such as diabetes and obesity. Furthermore, the invention relates to a process for preparing a pharmaceutical composition according to the invention, characterized in that a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of a compound of Formula (I), a pharmaceutically acceptable addition salt, or a solvate thereof.

The invention also relates to a product comprising a compound of Formula (I), a pharmaceutically acceptable addition salt, or a solvate thereof, and an additional pharmaceutical agent, as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of cancer, inflammatory disorders, autoimmune disorders, and metabolic disorders such as diabetes and obesity. Additionally, the invention relates to a method of treating or preventing a cell proliferative disease in a warm-blooded animal which comprises administering to the said animal an effective amount of a compound of Formula (I), a pharmaceutically acceptable addition salt, or a solvate thereof, as defined herein, or a pharmaceutical composition or combination as defined herein.

Some of the compounds of the present invention may undergo metabolism to a more active form in vivo (prodrugs).

DETAILED DESCRIPTION OF THE INVENTION

The term ‘halo’ or ‘halogen’ as used herein represents fluoro, chloro, bromo and iodo.

The prefix ‘C_(x-y)’ (where x and y are integers) as used herein refers to the number of carbon atoms in a given group. Thus, a C₁₋₆alkyl group contains from 1 to 6 carbon atoms, a C₃₋₆cycloalkyl group contains from 3 to 6 carbon atoms, and so on.

The term ‘C₁₋₄alkyl’ as used herein as a group or part of a group represents a straight or branched chain saturated hydrocarbon radical having from 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl and the like.

The term ‘C₁₋₆alkyl’ as used herein as a group or part of a group represents a straight or branched chain saturated hydrocarbon radical having from 1 to 6 carbon atoms such as the groups defined for C₁₋₄alkyl and n-pentyl, n-hexyl, 2-methylbutyl and the like.

The term “C₂₋₆alkenyl” as used herein as a group or part of a group represents a straight or branched chain hydrocarbon group containing from 2 to 6 carbon atoms and containing a carbon carbon double bond such as, but not limited to, ethenyl, propenyl, butenyl, pentenyl, 1-propen-2-yl, hexenyl and the like.

The term “C₂₋₆alkynyl” as used herein as a group or part of a group represents a straight or branched chain hydrocarbon group having from 2 to 6 carbon atoms and containing a carbon carbon triple bond.

The term ‘C₃₋₆cycloalkyl’ as used herein as a group or part of a group represents cyclic saturated hydrocarbon radicals having from 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In general, whenever the term “substituted” is used in the present invention, it is meant, unless otherwise is indicated or is clear from the context, to indicate that one or more hydrogens, in particular from 1 to 4 hydrogens, more in particular from 1 to 3 hydrogens, preferably 1 or 2 hydrogens, more preferably 1 hydrogen, on the atom or radical indicated in the expression using “substituted” are replaced with a selection from the indicated group, provided that the normal valency is not exceeded, and that the substitution results in a chemically stable compound, i.e. a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into a therapeutic agent.

Combinations of substituents and/or variables are permissible only if such combinations result in chemically stable compounds. “Stable compound” is meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into a therapeutic agent.

The skilled person will understand that the term “optionally substituted” means that the atom or radical indicated in the expression using “optionally substituted” may or may not be substituted (this means substituted or unsubstituted respectively).

When two or more substituents are present on a moiety they may, where possible and unless otherwise is indicated or is clear from the context, replace hydrogens on the same atom or they may replace hydrogen atoms on different atoms in the moiety.

It will be clear for the skilled person that, unless otherwise is indicated or is clear from the context, a substituent on a heterocyclyl group may replace any hydrogen atom on a ring carbon atom or on a ring heteroatom (e.g. a hydrogen on a nitrogen atom may be replaced by a substituent), for example in saturated heterocyclyl groups or 5-membered aromatic rings as used in the definition of R¹⁸.

C(O) or C(═O) represents a carbonyl moiety.

S(═O)₂ or SO₂ represents a sulfonyl moiety.

The skilled person will understand that —S(═O)(═N—R^(20a))—C₁₋₄alkyl corresponds with

Within the context of this invention ‘saturated’ means ‘fully saturated’, if not otherwise specified.

Het^(1a), Het^(1c) and Het^(1d), may be attached to the remainder of the molecule of Formula (I) through any available ring carbon or nitrogen atom as appropriate, if not otherwise specified.

The 5-membered aromatic ring containing one, two or three N-atoms as referred to in the definition of R¹⁸, may be attached to the remainder of the molecule of Formula (I) through any available ring carbon or nitrogen atom as, if not otherwise specified.

It will be clear that in case a saturated cyclic moiety is substituted on two ring carbon atoms with one substituent, in total two carbon-linked substituents are present on the saturated cyclic moiety (one substituent on each carbon atom).

It will be clear that in case a saturated cyclic moiety is substituted on two ring carbon atoms with two substituents, in total four carbon-linked substituents are present on the saturated cyclic moiety (two substituents on each carbon atom).

It will be clear that in case a saturated cyclic moiety is substituted on three ring carbon atoms with two substituents, in total six carbon-linked substituents are present on the saturated cyclic moiety (two substituents on each carbon atom).

It will be clear that in case a saturated cyclic moiety is substituted on two ring N-atoms with a substituent, in total two N-linked substituents are present on the saturated cyclic moiety (a substituent on each N-atom).

It will be clear that a saturated cyclic moiety may, where possible, have substituents on both carbon and N-atoms, unless otherwise is indicated or is clear from the context.

It will also be clear that R³ representing 2-oxo-1,2-dihydropyridin-3-yl, may have substituents on both carbon and N-atoms, unless otherwise is indicated or is clear from the context.

Within the context of this invention, bicyclic saturated heterocyclyl groups include fused, spiro and bridged saturated heterocycles.

Fused bicyclic groups are two cycles that share two atoms and the bond between these atoms.

Spiro bicyclic groups are two cycles that are joined at a single atom.

Bridged bicyclic groups are two cycles that share more than two atoms.

Examples of N-linked 6- to 11-membered fused bicyclic saturated heterocyclyl groups, include, but are not limited to

and the like.

Examples of N-linked 6- to 11-membered spiro bicyclic saturated heterocyclyl groups, include, but are not limited to

and the like.

Examples of N-linked 6- to 11-membered bridged bicyclic saturated heterocyclyl groups, include, but are not limited to

and the like.

The skilled person will realize that the definition of Het^(1a), Het^(1c) and Het^(1d) also includes C-linked bicycles (attached to the remainder of the molecule of Formula (I) through any available ring carbon atom).

It should be understood that the exemplified bicyclic saturated heterocyclyl groups referred to above may optionally be substituted, where possible, on carbon and/or nitrogen atoms according to any of the embodiments.

Non-limiting examples of 4- to 7-membered monocyclic saturated heterocyclyl moieties containing one or two heteroatoms each independently selected from O, S, S(═O) and N (as in the definition of Het^(1a), Het^(1c), and Het^(1d)) are shown below:

and the like.

Each of which may optionally be substituted, where possible, on carbon and/or nitrogen atoms according to any of the embodiments.

Non-limiting examples of 4- to 7-membered monocyclic saturated heterocyclyl moieties, attached to the remainder of the molecule of Formula (I) through any available ring carbon atom (C-linked), and containing one or two heteroatoms each independently selected from O, S, S(═O), and N (as in the definition of Het^(1b), Het^(1e), Het^(1g), Het⁴, Het⁷ and Het⁸) are shown below:

and the like.

Each of which may optionally be substituted, where possible, on carbon and/or nitrogen atoms according to any of the embodiments.

Non-limiting examples of N-linked 4- to 7-membered monocyclic saturated heterocyclyl moieties optionally containing one additional heteroatom selected from O, S, S(═O)_(p) and N (as in the definition of (b-1) and (c-1)) are shown below:

and the like.

Each of which may optionally be substituted, where possible, on carbon and/or nitrogen atoms according to any of the embodiments.

Non-limiting examples of 5-membered aromatic ring containing one, two or three N-atoms as referred to in the definition of R¹⁸ are shown below:

and the like.

Each of which may optionally be substituted, where possible, on carbon and/or nitrogen atoms according to any of the embodiments.

Non-limiting examples of 6-membered heteroaromatic rings containing 1 or 2 N-atoms (as in the definition of R³) are pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl; particular non-limiting examples are 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 5-pyrimidinyl, 4-pyrimidinyl, 4-pyridazinyl or 2-pyrazinyl; each of which may optionally be substituted according to any of the embodiments.

Whenever substituents are represented by chemical structure, “- - -” represents the bond of attachment to the remainder of the molecule of Formula (I).

Lines (such as “- - -”) drawn into ring systems indicate that the bond may be attached to any of the suitable ring atoms.

When any variable occurs more than one time in any constituent, each definition is independent.

When any variable occurs more than one time in any formula (e.g. Formula (I)), each definition is independent.

The term “subject” as used herein, refers to an animal, preferably a mammal (e.g. cat, dog, primate or human), more preferably a human, who is or has been the object of treatment, observation or experiment.

The term “therapeutically effective amount” as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medicinal doctor or other clinician, which includes alleviation or reversal of the symptoms of the disease or disorder being treated.

The term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.

The term “treatment”, as used herein, is intended to refer to all processes wherein there may be a slowing, interrupting, arresting or stopping of the progression of a disease, but does not necessarily indicate a total elimination of all symptoms.

The term “compound(s) of the (present) invention” or “compound(s) according to the (present) invention” as used herein, is meant to include the compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof.

As used herein, any chemical formula with bonds shown only as solid lines and not as solid wedged or hashed wedged bonds, or otherwise indicated as having a particular configuration (e.g. R, S) around one or more atoms, contemplates each possible stereoisomer, or mixture of two or more stereoisomers.

Hereinbefore and hereinafter, the term “compound(s) of Formula (I)” is meant to include the tautomers thereof and the stereoisomeric forms thereof.

The terms “stereoisomers”, “stereoisomeric forms” or “stereochemically isomeric forms” hereinbefore or hereinafter are used interchangeably.

The invention includes all stereoisomers of the compounds of the invention either as a pure stereoisomer or as a mixture of two or more stereoisomers.

Enantiomers are stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a racemate or racemic mixture.

Atropisomers (or atropoisomers) are stereoisomers which have a particular spatial configuration, resulting from a restricted rotation about a single bond, due to large steric hindrance. All atropisomeric forms of the compounds of Formula (I) are intended to be included within the scope of the present invention.

Diastereomers (or diastereoisomers) are stereoisomers that are not enantiomers, i.e. they are not related as mirror images. If a compound contains a double bond, the substituents may be in the E or the Z configuration.

Substituents on bivalent cyclic saturated or partially saturated radicals may have either the cis- or trans-configuration; for example if a compound contains a disubstituted cycloalkyl group, the substituents may be in the cis or trans configuration.

Therefore, the invention includes enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof, whenever chemically possible.

The meaning of all those terms, i.e. enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof are known to the skilled person.

The absolute configuration is specified according to the Cahn-Ingold-Prelog system. The configuration at an asymmetric atom is specified by either R or S. Resolved stereoisomers whose absolute configuration is not known can be designated by (+) or (−) depending on the direction in which they rotate plane polarized light. For instance, resolved enantiomers whose absolute configuration is not known can be designated by (+) or (−) depending on the direction in which they rotate plane polarized light.

When a specific stereoisomer is identified, this means that said stereoisomer is substantially free, i.e. associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, in particular less than 2% and most preferably less than 1%, of the other stereoisomers. Thus, when a compound of Formula (I) is for instance specified as (R), this means that the compound is substantially free of the (S) isomer; when a compound of Formula (I) is for instance specified as E, this means that the compound is substantially free of the Z isomer; when a compound of Formula (I) is for instance specified as cis, this means that the compound is substantially free of the trans isomer.

Some of the compounds according to Formula (I) may also exist in their tautomeric form. Such forms in so far as they may exist, although not explicitly indicated in the above Formula (I) are intended to be included within the scope of the present invention.

It follows that a single compound may exist in both stereoisomeric and tautomeric form.

Pharmaceutically-acceptable addition salts include acid addition salts and base addition salts. Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound of the invention in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.

The pharmaceutically acceptable addition salts as mentioned hereinabove or hereinafter are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the compounds of Formula (I) and solvates thereof, are able to form.

Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids. Conversely said salt forms can be converted by treatment with an appropriate base into the free base form.

The compounds of Formula (I) and solvates thereof containing an acidic proton may also be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases.

Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. primary, secondary and tertiary aliphatic and aromatic amines such as methylamine, ethylamine, propylamine, isopropylamine, the four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline; the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like. Conversely the salt form can be converted by treatment with acid into the free acid form.

The term solvate comprises the solvent addition forms as well as the salts thereof, which the compounds of Formula (I) are able to form. Examples of such solvent addition forms are e.g. hydrates, alcoholates and the like.

The compounds of the invention as prepared in the processes described below may be synthesized in the form of mixtures of enantiomers, in particular racemic mixtures of enantiomers, that can be separated from one another following art-known resolution procedures. A manner of separating the enantiomeric forms of the compounds of Formula (I), and pharmaceutically acceptable addition salts, and solvates thereof, involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably if a specific stereoisomer is desired, said compound would be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.

The present invention also embraces isotopically-labeled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (or the most abundant one found in nature).

All isotopes and isotopic mixtures of any particular atom or element as specified herein are contemplated within the scope of the compounds of the invention, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵O, ¹⁷O, ¹⁸O, ³²P, ³³P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²²I, ¹²³I, ¹²⁵I, ¹³¹I, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br and ⁸²Br. Preferably, the radioactive isotope is selected from the group of ²H, ³H, ¹¹C and ¹⁸F. More preferably, the radioactive isotope is ²H. In particular, deuterated compounds are intended to be included within the scope of the present invention.

Certain isotopically-labeled compounds of the present invention (e.g., those labeled with ³H and ¹⁴C) are useful in compound and for substrate tissue distribution assays. Tritiated (³H) and carbon-14 (¹⁴C) isotopes are useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., ²H may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Positron emitting isotopes such as ¹⁵O, ¹³N, ¹¹C and ¹⁸F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy.

The present invention relates in particular to compounds of Formula (I) as defined herein, tautomers and stereoisomeric forms thereof, wherein

R¹ represents C₁₋₄alkyl;

R² represents C₁₋₆alkyl, or C₁₋₆alkyl substituted with one R⁵;

Y represents CR⁴ or N;

R⁴ represents hydrogen or halo;

R⁵ represents halo, Het^(3a), —NR^(6a)R^(6b), or —OR⁷;

R^(6a) represents hydrogen or C₁₋₄alkyl;

R^(6b) represents hydrogen; C₁₋₄alkyl; C₃₋₆cycloalkyl; —C(═O)—C₁₋₄alkyl; —C(═O)—Het⁴; —S(═O)₂—C₁₋₄alkyl; —C(═O)—C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —NR^(16a)R^(16b); or C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —S(═O)₂—C₁₋₄alkyl; R⁷ represents hydrogen, C₁₋₄alkyl, —C₁₋₄alkyl-NR^(8a)R^(8b), —C(═O)—R⁹, —S(═O)₂—OH, —P(═O)₂—OH, —(C═O)—CH(NH₂)—C₁₋₄alkyl-Ar¹, or —C₁₋₄alkyl-Het^(3b); R^(8a) represents hydrogen or C₁₋₄alkyl; R^(8b) represents hydrogen, C₁₋₄alkyl, or C₃₋₆cycloalkyl; R⁹ represents C₁₋₆alkyl, or C₁₋₆alkyl substituted with one substituent selected from the group consisting of —NH₂, —COOH, and Het⁶; R^(16a) and R^(16b) each independently represents hydrogen, C₁₋₄alkyl or C₃₋₆cycloalkyl; R³ represents 2-oxo-1,2-dihydropyridin-3-yl, wherein said 2-oxo-1,2-dihydropyridin-3-yl may optionally be substituted on the N-atom with a substituent selected from the group consisting of C₁₋₆alkyl; C₃₋₆cycloalkyl; Het^(1a); R¹⁸; R²¹; C₁₋₄alkyl substituted with one, two or three halo atoms; C₁₋₄alkyl substituted with one, two or three —OH substituents; C₁₋₄alkyl substituted with one R¹³; C₁₋₄alkyl substituted with one R¹⁸; C₂₋₆alkenyl; and C₂₋₆alkenyl substituted with one R¹³; provided that when Het^(1a) or R¹⁸ are directly attached to the N-atom of the 2-oxo-1,2-dihydropyridin-3-yl, said Het^(1a) or R¹⁸ are attached to the N-atom via a ring carbon atom; and

wherein said 2-oxo-1,2-dihydropyridin-3-yl may optionally be substituted on the ring carbon atoms with in total one, two or three substituents each independently selected from the group consisting of halo; cyano; C₁₋₆alkyl; —O—C₁₋₄alkyl; —C(═O)—R¹⁰; —S(═O)₂—C₁₋₄alkyl; —S(═O)(═N—R^(20a))—C₁₋₄alkyl; —O—C₁₋₄alkyl substituted with one, two or three halo atoms; —O—C₁₋₄alkyl-R¹²; C₃₋₆cycloalkyl; —O—C₃₋₆cycloalkyl; Het^(1a); —O-Het^(1b); R¹⁸; R²¹; —P(═O)—(C₁₋₄alkyl)₂; —NH—C(═O)—C₁₋₄alkyl; —NH—C(═O)—Het^(1g); —NR^(17a)R^(17b); C₁₋₄alkyl substituted with one, two or three halo atoms; C₁₋₄alkyl substituted with one, two or three —OH substituents; C₁₋₄alkyl substituted with one R¹³; C₁₋₄alkyl substituted with one R¹⁸; C₂₋₆alkenyl; C₂₋₆alkenyl substituted with one R¹³; C₂₋₆alkynyl; and C₂₋₆alkynyl substituted with one R¹³;

R¹⁰ represents —OH, —O—C₁₋₄alkyl, —NR^(11a)R^(11b) or Het²;

R¹⁸ represents a 5-membered aromatic ring containing one, two or three N-atoms; wherein said 5-membered aromatic ring may optionally be substituted with one substituent selected from the group consisting of C₁₋₄alkyl and C₃₋₆cycloalkyl;

R²¹ represents 3,6-dihydro-2H-pyran-4-yl or 1,2,3,6-tetrahydro-4-pyridinyl, wherein 1,2,3,6-tetrahydro-4-pyridinyl may optionally be substituted on the N-atom with C₁₋₄alkyl or C₃₋₆cycloalkyl;

Het^(1a), Het^(1c) and Het^(1d) each independently represents a 4- to 7-membered monocyclic saturated heterocyclyl containing one or two heteroatoms each independently selected from O, S, S(═O)_(p) and N; or a 6- to 11-membered bicyclic saturated heterocyclyl, including fused, spiro and bridged cycles, containing one, two or three heteroatoms each independently selected from O, S, S(═O)_(p) and N; wherein said 4- to 7-membered monocyclic saturated heterocyclyl or said 6- to 11-membered bicyclic saturated heterocyclyl may optionally be substituted, where possible, on one, two or three ring N-atoms with a substituent each independently selected from the group consisting of C₁₋₄alkyl, C₃₋₆cycloalkyl, and C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —O—C₁₋₄alkyl; and wherein said 4- to 7-membered monocyclic saturated heterocyclyl or said 6- to 11-membered bicyclic saturated heterocyclyl may optionally be substituted on one, two or three ring C-atoms with one or two substituents each independently selected from the group consisting of —OH, halo, C₁₋₄alkyl, cyano, —C(═O)—C₁₋₄alkyl, —O—C₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)₂; Het^(1b), Het^(1e), Het^(1g), Het⁴, Het⁷ and Het⁸ each independently represents a 4- to 7-membered monocyclic saturated heterocyclyl, attached to the remainder of the molecule of Formula (I) through any available ring carbon atom, said Het^(1b), Het^(1e), Het^(1g), Het⁴, Het⁷ and Het⁸ containing one or two heteroatoms each independently selected from O, S, S(═O)_(p) and N; wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted, where possible, on one or two ring N-atoms with a substituent each independently selected from the group consisting of C₁₋₄alkyl, C₃₋₆cycloalkyl, and C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —O—C₁₋₄alkyl; and wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted on one, two or three ring C-atoms with one or two substituents each independently selected from the group consisting of —OH, halo, C₁₋₄alkyl, cyano, —C(═O)—C₁₋₄alkyl, —O—C₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)₂; Het² represents a heterocyclyl of formula (b-1):

(b-1) represents a N-linked 4- to 7-membered monocyclic saturated heterocyclyl optionally containing one additional heteroatom selected from O, S, S(═O)_(p) and N, or a N-linked 6- to 11-membered bicyclic saturated heterocyclyl, including fused, spiro and bridged cycles, optionally containing one or two additional heteroatoms each independently selected from O, S, S(═O)_(p) and N; wherein in case (b-1) contains one or two additional N-atoms, said one or two N-atoms may optionally be substituted with a substituent each independently selected from the group consisting of C₁₋₄alkyl, C₃₋₆cycloalkyl and Het⁷; and wherein (b-1) may optionally be substituted on one, two or three ring C-atoms with one or two substituents each independently selected from the group consisting of halo, —OH, cyano, C₁₋₄alkyl, —O—C₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, and C₁₋₄alkyl-OH;

-   -   R^(11b) represents hydrogen; Het^(1e); C₁₋₄alkyl;         —C₁₋₄alkyl-Het⁵; —C₁₋₄alkyl-Het⁸; C₁₋₄alkyl substituted with         one, two or three substituents each independently selected from         the group consisting of halo, —OH and —O—C₁₋₄alkyl;         C₃₋₆cycloalkyl; or C₃₋₆cycloalkyl substituted with one, two or         three substituents each independently selected from the group         consisting of halo,         —OH and —O—C₁₋₄alkyl;         R¹³ represents —O—C₁₋₄alkyl, —C(═O)NR^(15a)R^(15b),         —NR^(19a)R^(19b), C₃₋₆cycloalkyl, Het^(1d), or —C(═O)—Het^(1f);         R¹² represents —OH, —O—C₁₋₄alkyl, —NR^(14a)R^(14b),         —C(═O)NR^(14c)R^(14d), —S(═O)₂—C₁₋₄alkyl,         —S(═O)(═N—R^(20b))—C₁₋₄alkyl, C₃₋₆cycloalkyl, Ar², or Het^(1c);         Ar¹ represents phenyl optionally substituted with one hydroxy;         Ar² represents phenyl optionally substituted with one C₁₋₄alkyl;         Het^(3a), Het^(3b), Het⁵, Het⁶ and Het^(1f) each independently         represents a heterocyclyl of formula (c-1):

(c-1) represents a N-linked 4- to 7-membered monocyclic saturated heterocyclyl optionally containing one additional heteroatom selected from O, S, S(═O)_(p) and N; wherein in case (c-1) contains one additional N-atom, said additional N-atom may optionally be substituted with C₁₋₄alkyl or C₃₋₆cycloalkyl; and wherein (c-1) may optionally be substituted on one or two ring C-atoms atoms with one or two substituents each independently selected from the group consisting of halo, C₁₋₄alkyl, and C₃₋₆cycloalkyl; R^(11a), R^(14a), R^(14c), R^(15a), R^(17b) and R^(19a) each independently represents hydrogen or C₁₋₄alkyl; R^(14b), R^(14d), R^(15b), R^(17b) and R^(19b) each independently represents hydrogen; C₁₋₄alkyl; C₃₋₆cycloalkyl; —C(═O)—C₁₋₄alkyl; C₁₋₄alkyl substituted with one substituent selected from the group consisting of halo, —OH and —O—C₁₋₄alkyl; —C(═O)—C₁₋₄alkyl substituted with one substituent selected from the group consisting of halo, —OH and —O—C₁₋₄alkyl; or —S(═O)₂—C₁₋₄alkyl; R^(20a) and R^(20b) each independently represents hydrogen; C₁₋₄alkyl; C₃₋₆cycloalkyl; or C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —O—C₁₋₄alkyl; p represents 1 or 2; and the pharmaceutically acceptable addition salts, and the solvates thereof.

The present invention relates in particular to compounds of Formula (I) as defined herein, tautomers and stereoisomeric forms thereof, wherein

R¹ represents C₁₋₄alkyl;

R² represents C₁₋₆alkyl, or C₁₋₆alkyl substituted with one R⁵;

Y represents CR⁴ or N;

R⁴ represents hydrogen or halo;

R⁵ represents halo, Het^(3a), —NR^(6a)R^(6b), or —OR⁷;

R^(6a) represents hydrogen or C₁₋₄alkyl;

R^(6b) represents hydrogen; C₁₋₄alkyl; C₃₋₆cycloalkyl; —C(═O)—C₁₋₄alkyl; —C(═O)—Het⁴; —S(═O)₂—C₁₋₄alkyl; —C(═O)—C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —NR^(16a)R^(16b); or C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —S(═O)₂—C₁₋₄alkyl; R⁷ represents hydrogen, C₁₋₄alkyl, —C₁₋₄alkyl-NR^(8a)R^(8b), —C(═O)—R⁹, —S(═O)₂—OH, —P(═O)₂—OH, —(C═O)—CH(NH₂)—C₁₋₄alkyl-Ar, or —C₁₋₄alkyl-Het^(3b); R^(8a) represents hydrogen or C₁₋₄alkyl; R^(8b) represents hydrogen, C₁₋₄alkyl, or C₃₋₆cycloalkyl; R⁹ represents C₁₋₆alkyl, or C₁₋₆alkyl substituted with one substituent selected from the group consisting of —NH₂, —COOH, and Het⁶; R^(16a) and R^(16b) each independently represents hydrogen, C₁₋₄alkyl or C₃₋₆cycloalkyl; R³ represents a 6-membered heteroaromatic ring containing 1 or 2 N-atoms, optionally substituted with one, two or three substituents each independently selected from the group consisting of halo; cyano; C₁₋₆alkyl; —O—C₁₋₄alkyl; —C(═O)—R¹⁰; —S(═O)₂—C₁₋₄alkyl; —S(═O)(═N—R^(20a))—C₁₋₄alkyl; —O—C₁₋₄alkyl substituted with one, two or three halo atoms; —O—C₁₋₄alkyl-R¹²; C₃₋₆cycloalkyl; —O—C₃₋₆cycloalkyl; Het^(1a); —O-Het^(1b); R¹⁸; R²¹; —P(═O)—(C₁₋₄alkyl)₂; —NH—C(═O)—C₁₋₄alkyl; —NH—C(═O)—Het^(1g); —NR^(17a)R^(17b); C₁₋₄alkyl substituted with one, two or three halo atoms; C₁₋₄alkyl substituted with one, two or three —OH substituents; C₁₋₄alkyl substituted with one R¹³; C₁₋₄alkyl substituted with one R¹⁸; C₂₋₆alkenyl; C₂₋₆alkenyl substituted with one R¹³; C₂₋₆alkynyl; and C₂₋₆alkynyl substituted with one R¹³; R¹⁰ represents —OH, —O—C₁₋₄alkyl, —NR^(11a)R^(11b) or Het²; R¹⁸ represents a 5-membered aromatic ring containing one, two or three N-atoms; wherein said 5-membered aromatic ring may optionally be substituted with one substituent selected from the group consisting of C₁₋₄alkyl and C₃₋₆cycloalkyl; R²¹ represents 3,6-dihydro-2H-pyran-4-yl or 1,2,3,6-tetrahydro-4-pyridinyl, wherein 1,2,3,6-tetrahydro-4-pyridinyl may optionally be substituted on the N-atom with C₁₋₄alkyl or C₃₋₆cycloalkyl; Het^(1a), Het^(1c) and Het^(1d) each independently represents a 4- to 7-membered monocyclic saturated heterocyclyl containing one or two heteroatoms each independently selected from O, S, S(═O)_(p) and N; or a 6- to 11-membered bicyclic saturated heterocyclyl, including fused, spiro and bridged cycles, containing one, two or three heteroatoms each independently selected from O, S, S(═O)_(p) and N; wherein said 4- to 7-membered monocyclic saturated heterocyclyl or said 6- to 11-membered bicyclic saturated heterocyclyl may optionally be substituted, where possible, on one, two or three ring N-atoms with a substituent each independently selected from the group consisting of C₁₋₄alkyl, C₃₋₆cycloalkyl, and C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —O—C₁₋₄alkyl; and wherein said 4- to 7-membered monocyclic saturated heterocyclyl or said 6- to 11-membered bicyclic saturated heterocyclyl may optionally be substituted on one, two or three ring C-atoms with one or two substituents each independently selected from the group consisting of —OH, halo, C₁₋₄alkyl, cyano, —C(═O)—C₁₋₄alkyl, —O—C₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)₂; Het^(1b), Het^(1e), Het^(1g), Het⁴, Het⁷ and Het⁸ each independently represents a 4- to 7-membered monocyclic saturated heterocyclyl, attached to the remainder of the molecule of Formula (I) through any available ring carbon atom, said Het^(1b), Het^(1e), Het^(1g), Het⁴, Het⁷ and Het⁸ containing one or two heteroatoms each independently selected from O, S, S(═O)_(p) and N; wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted, where possible, on one or two ring N-atoms with a substituent each independently selected from the group consisting of C₁₋₄alkyl, C₃₋₆cycloalkyl, and C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —O—C₁₋₄alkyl; and wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted on one, two or three ring C-atoms with one or two substituents each independently selected from the group consisting of —OH, halo, C₁₋₄alkyl, cyano, —C(═O)—C₁₋₄alkyl, —O—C₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)₂; Het² represents a heterocyclyl of formula (b-1):

(b-1) represents a N-linked 4- to 7-membered monocyclic saturated heterocyclyl optionally containing one additional heteroatom selected from O, S, S(═O)_(p) and N, or a N-linked 6- to 11-membered bicyclic saturated heterocyclyl, including fused, spiro and bridged cycles, optionally containing one or two additional heteroatoms each independently selected from O, S, S(═O)_(p) and N; wherein in case (b-1) contains one or two additional N-atoms, said one or two N-atoms may optionally be substituted with a substituent each independently selected from the group consisting of C₁₋₄alkyl, C₃₋₆cycloalkyl and Het⁷; and wherein (b-1) may optionally be substituted on one, two or three ring C-atoms with one or two substituents each independently selected from the group consisting of halo, —OH, cyano, C₁₋₄alkyl, —O—C₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, and C₁₋₄alkyl-OH;

-   -   R^(11b) represents hydrogen; Het^(1e); C₁₋₄alkyl;         —C₁₋₄alkyl-Het⁵; —C₁₋₄alkyl-Het⁸; C₁₋₄alkyl substituted with         one, two or three substituents each independently selected from         the group consisting of halo, —OH and —O—C₁₋₄alkyl;         C₃₋₆cycloalkyl; or C₃₋₆cycloalkyl substituted with one, two or         three substituents each independently selected from the group         consisting of halo,         —OH and —O—C₁₋₄alkyl;         R¹³ represents —O—C₁₋₄alkyl, —C(═O)NR^(15a)R^(15b),         —NR^(19a)R^(19b), C₃₋₆cycloalkyl, Het^(1d), or —C(═O)—Het^(1f);         R¹² represents —OH, —O—C₁₋₄alkyl, —NR^(14a)R^(14b),         —C(═O)NR^(14c)R^(14d), —S(═O)₂—C₁₋₄alkyl,         —S(═O)(═N—R^(20b))—C₁₋₄alkyl, C₃₋₆cycloalkyl, Ar², or Het^(1c);         Ar¹ represents phenyl optionally substituted with one hydroxy;         Ar² represents phenyl optionally substituted with one C₁₋₄alkyl;         Het^(3a), Het^(3b), Het⁵, Het⁶ and Het^(1f) each independently         represents a heterocyclyl of formula (c-1):

(c-1) represents a N-linked 4- to 7-membered monocyclic saturated heterocyclyl optionally containing one additional heteroatom selected from O, S, S(═O)_(p) and N; wherein in case (c-1) contains one additional N-atom, said additional N-atom may optionally be substituted with C₁₋₄alkyl or C₃₋₆cycloalkyl; and wherein (c-1) may optionally be substituted on one or two ring C-atoms atoms with one or two substituents each independently selected from the group consisting of halo, C₁₋₄alkyl, and C₃₋₆cycloalkyl; R^(11a), R^(14a), R^(14c), R^(15a), R^(17a) and R^(19a) each independently represents hydrogen or C₁₋₄alkyl; R^(14b), R^(14d), R^(15b), R^(17b) and R^(19b) each independently represents hydrogen; C₁₋₄alkyl; C₃₋₆cycloalkyl; —C(═O)—C₁₋₄alkyl; C₁₋₄alkyl substituted with one substituent selected from the group consisting of halo, —OH and —O—C₁₋₄alkyl; —C(═O)—C₁₋₄alkyl substituted with one substituent selected from the group consisting of halo, —OH and —O—C₁₋₄alkyl; or —S(═O)₂—C₁₋₄alkyl; R^(20a) and R^(20b) each independently represents hydrogen; C₁₋₄alkyl; C₃₋₆cycloalkyl; or C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —O—C₁₋₄alkyl; p represents 1 or 2; and the pharmaceutically acceptable addition salts, and the solvates thereof.

The present invention relates in particular to compounds of Formula (I) as defined herein, tautomers and stereoisomeric forms thereof, wherein

R¹ represents C₁₋₄alkyl;

R² represents C₁₋₆alkyl, or C₁₋₆alkyl substituted with one R⁵;

Y represents CR⁴;

R⁴ represents hydrogen or halo;

R⁵ represents Het^(3a), —NR^(6a)R^(6b), or —OR⁷;

R^(6a) represents hydrogen or C₁₋₄alkyl;

R^(6b) represents hydrogen; C₁₋₄alkyl; C₃₋₆cycloalkyl; —C(═O)—C₁₋₄alkyl; —C(═O)—Het⁴; —S(═O)₂—C₁₋₄alkyl; —C(═O)—C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —NR^(16a)R^(16b); or C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —S(═O)₂—C₁₋₄alkyl; R⁷ represents hydrogen, C₁₋₄alkyl, —C₁₋₄alkyl-NR^(8a)R^(8b), —C(═O)—R⁹, —S(═O)₂—OH, —P(═O)₂—OH, —(C═O)—CH(NH₂)—C₁₋₄alkyl-Ar¹, or —C₁₋₄alkyl-Het^(3b); R^(sa) represents hydrogen or C₁₋₄alkyl; R^(8b) represents hydrogen, C₁₋₄alkyl, or C₃₋₆cycloalkyl; R⁹ represents C₁₋₆alkyl, or C₁₋₆alkyl substituted with one substituent selected from the group consisting of —NH₂, —COOH, and Het⁶; R^(16a) and R^(16b) each independently represents hydrogen, C₁₋₄alkyl or C₃₋₆cycloalkyl; R³ represents a 6-membered heteroaromatic ring containing 1 or 2 N-atoms, optionally substituted with one, two or three substituents each independently selected from the group consisting of halo; cyano; C₁₋₆alkyl; —O—C₁₋₄alkyl; —C(═O)—R¹⁰; —S(═O)₂—C₁₋₄alkyl; —S(═O)(═N—R^(20a))—C₁₋₄alkyl; —O—C₁₋₄alkyl substituted with one, two or three halo atoms; —O—C₁₋₄alkyl-R¹²; C₃₋₆cycloalkyl; —O—C₃₋₆cycloalkyl; Het^(1a); —O-Het^(1b); R¹⁸; R²¹; —P(═O)—(C₁₋₄alkyl)₂; —NH—C(═O)—C₁₋₄alkyl; —NH—C(═O)—Het^(1g); —NR^(17a)R^(17b); C₁₋₄alkyl substituted with one, two or three halo atoms; C₁₋₄alkyl substituted with one, two or three —OH substituents; C₁₋₄alkyl substituted with one R¹³; C₁₋₄alkyl substituted with one R¹⁸; C₂₋₆alkenyl; and C₂₋₆alkenyl substituted with one R¹³; or R³ represents 2-oxo-1,2-dihydropyridin-3-yl, wherein said 2-oxo-1,2-dihydropyridin-3-yl may optionally be substituted on the N-atom with a substituent selected from the group consisting of C₁₋₆alkyl; C₃₋₆cycloalkyl; Het^(1a); R¹⁸; R²¹; C₁₋₄alkyl substituted with one, two or three halo atoms; C₁₋₄alkyl substituted with one, two or three —OH substituents; C₁₋₄alkyl substituted with one R¹³; C₁₋₄alkyl substituted with one R¹⁸; C₂₋₆alkenyl; and C₂₋₆alkenyl substituted with one R¹³; provided that when Het^(1a) or R¹⁸ are directly attached to the N-atom of the 2-oxo-1,2-dihydropyridin-3-yl, said Het^(1a) or R¹⁸ are attached to the N-atom via a ring carbon atom; and wherein said 2-oxo-1,2-dihydropyridin-3-yl may optionally be substituted on the ring carbon atoms with in total one, two or three substituents each independently selected from the group consisting of halo; cyano; C₁₋₆alkyl; —O—C₁₋₄alkyl; —C(═O)—R¹⁰; —S(═O)₂—C₁₋₄alkyl; —S(═O)(═N—R^(20a))—C₁₋₄alkyl; —O—C₁₋₄alkyl substituted with one, two or three halo atoms; —O—C₁₋₄alkyl-R¹²; C₃₋₆cycloalkyl; —O—C₃₋₆cycloalkyl; Het^(1a); —O-Het^(1b); R¹⁸; R²¹; —P(═O)—(C₁₋₄alkyl)₂; —NH—C(═O)—C₁₋₄alkyl; —NH—C(═O)—Het^(1g); —NR^(17a)R^(17b); C₁₋₄ alkyl substituted with one, two or three halo atoms; C₁₋₄alkyl substituted with one, two or three —OH substituents; C₁₋₄alkyl substituted with one R¹³; C₁₋₄alkyl substituted with one R¹⁸; C₂₋₆alkenyl; and C₂₋₆alkenyl substituted with one R¹³; R¹⁰ represents —OH, —O—C₁₋₄alkyl, —NR 11^(a)R^(11b) or Het²; R¹⁸ represents a 5-membered aromatic ring containing one, two or three N-atoms; wherein said 5-membered aromatic ring may optionally be substituted with one substituent selected from the group consisting of C₁₋₄alkyl and C₃₋₆cycloalkyl; R²¹ represents 3,6-dihydro-2H-pyran-4-yl or 1,2,3,6-tetrahydro-4-pyridinyl, wherein 1,2,3,6-tetrahydro-4-pyridinyl may optionally be substituted on the N-atom with C₁₋₄alkyl or C₃₋₆cycloalkyl; Het^(1a), Het^(1c) and Het^(1d) each independently represents a 4- to 7-membered monocyclic saturated heterocyclyl containing one or two heteroatoms each independently selected from O, S, S(═O)_(p) and N; or a 6- to 11-membered bicyclic saturated heterocyclyl, including fused, spiro and bridged cycles, containing one, two or three heteroatoms each independently selected from O, S, S(═O)_(p) and N; wherein said 4- to 7-membered monocyclic saturated heterocyclyl or said 6- to 11-membered bicyclic saturated heterocyclyl may optionally be substituted, where possible, on one, two or three ring N-atoms with a substituent each independently selected from the group consisting of C₁₋₄alkyl, C₃₋₆cycloalkyl, and C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —O—C₁₋₄alkyl; and wherein said 4- to 7-membered monocyclic saturated heterocyclyl or said 6- to 11-membered bicyclic saturated heterocyclyl may optionally be substituted on one, two or three ring C-atoms with one or two substituents each independently selected from the group consisting of —OH, halo, C₁₋₄alkyl, cyano, —C(═O)—C₁₋₄alkyl, —O—C₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)₂; Het^(1b), Het^(1e), Het^(1g) and Het⁴ each independently represents a 4- to 7-membered monocyclic saturated heterocyclyl, attached to the remainder of the molecule of Formula (I) through any available ring carbon atom, said Het^(1b), Het^(1e), Het^(1g) and Het⁴ containing one or two heteroatoms each independently selected from O, S, S(═O)_(p) and N; wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted, where possible, on one or two ring N-atoms with a substituent each independently selected from the group consisting of C₁₋₄alkyl, C₃₋₆cycloalkyl, and C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —O—C₁₋₄alkyl; and wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted on one, two or three ring C-atoms with one or two substituents each independently selected from the group consisting of —OH, halo, C₁₋₄alkyl, cyano, —C(═O)—C₁₋₄alkyl, —O—C₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)₂; Het² represents a heterocyclyl of formula (b-1):

(b-1) represents a N-linked 4- to 7-membered monocyclic saturated heterocyclyl optionally containing one additional heteroatom selected from O, S, S(═O)_(p) and N, or a N-linked 6- to 11-membered bicyclic saturated heterocyclyl, including fused, spiro and bridged cycles, optionally containing one or two additional heteroatoms each independently selected from O, S, S(═O)_(p) and N; wherein in case (b-1) contains one or two additional N-atoms, said one or two N-atoms may optionally be substituted with C₁₋₄alkyl; and wherein (b-1) may optionally be substituted on one, two or three ring C-atoms with one or two substituents each independently selected from the group consisting of halo, —OH, cyano, C₁₋₄alkyl, —O—C₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, and C₁₋₄alkyl-OH; R^(11b) represents hydrogen; Het^(1e); C₁₋₄alkyl; —C₁₋₄alkyl-Het⁵; C₁₋₄alkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, —OH and —O—C₁₋₄alkyl; C₃₋₆cycloalkyl; or C₃₋₆cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, —OH and —O—C₁₋₄alkyl; R¹³ represents —O—C₁₋₄alkyl, —C(═O)NR^(15a)R^(15b), —NR^(19a)R^(19b), C₃₋₆cycloalkyl, Het^(1d), or —C(═O)—Het^(1f); R¹² represents —OH, —O—C₁₋₄alkyl, —NR^(14a)R^(14b), —C(═O)NR^(14c)R^(14d), —S(═O)₂—C₁₋₄alkyl, —S(═O)(═N—R^(20b))—C₁₋₄alkyl, C₃₋₆cycloalkyl, Ar², or Het^(1c); Ar¹ represents phenyl optionally substituted with one hydroxy; Ar² represents phenyl optionally substituted with one C₁₋₄alkyl; Het^(3a), Het^(3b), Het⁵, Het⁶ and Het^(1f) each independently represents a heterocyclyl of formula (c-1):

(c-1) represents a N-linked 4- to 7-membered monocyclic saturated heterocyclyl optionally containing one additional heteroatom selected from O, S, S(═O)_(p) and N; wherein in case (c-1) contains one additional N-atom, said additional N-atom may optionally be substituted with C₁₋₄alkyl or C₃₋₆cycloalkyl; and wherein (c-1) may optionally be substituted on one or two ring C-atoms atoms with one or two substituents each independently selected from the group consisting of halo, C₁₋₄alkyl, and C₃₋₆cycloalkyl; R^(11a), R^(14a), R^(14c), R^(15a), R^(17a) and R^(19a) each independently represents hydrogen or C₁₋₄alkyl; R^(14b), R^(14d), R^(15b), R^(17b) and R^(19b) each independently represents hydrogen; C₁₋₄alkyl; C₃₋₆cycloalkyl; or C₁₋₄alkyl substituted with one substituent selected from the group consisting of halo, —OH and —O—C₁₋₄alkyl; R^(20a) and R^(20b) each independently represents hydrogen; C₁₋₄alkyl; C₃₋₆cycloalkyl; or C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —O—C₁₋₄alkyl; p represents 1 or 2; and the pharmaceutically acceptable addition salts, and the solvates thereof.

The present invention relates in particular to compounds of Formula (I) as defined herein, tautomers and stereoisomeric forms thereof, wherein

R¹ represents C₁₋₄alkyl;

R² represents C₁₋₆alkyl, or C₁₋₆alkyl substituted with one R⁵;

Y represents CR⁴;

R⁴ represents hydrogen or halo;

R⁵ represents Het^(3a), —NR^(6a)R^(6b), or —OR⁷;

R^(6a) represents hydrogen or C₁₋₄alkyl;

R^(6b) represents hydrogen; C₁₋₄alkyl; C₃₋₆cycloalkyl; —C(═O)—C₁₋₄alkyl; —C(═O)—Het⁴; —S(═O)₂—C₁₋₄alkyl; —C(═O)—C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —NR^(16a)R^(16b); or C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —S(═O)₂—C₁₋₄alkyl; R⁷ represents hydrogen, C₁₋₄alkyl, —C₁₋₄alkyl-NR^(8a)R^(8b), —C(═O)—R⁹, —S(═O)₂—OH, —P(═O)₂—OH, —(C═O)—CH(NH₂)—C₁₋₄alkyl-Ar¹, or —C₁₋₄alkyl-Het^(3b); R^(8a) represents hydrogen or C₁₋₄alkyl; R^(8b) represents hydrogen, C₁₋₄alkyl, or C₃₋₆cycloalkyl; R⁹ represents C₁₋₆alkyl, or C₁₋₆alkyl substituted with one substituent selected from the group consisting of —NH₂, —COOH, and Het⁶; R^(16a) and R^(16b) each independently represents hydrogen, C₁₋₄alkyl or C₃₋₆cycloalkyl; R³ represents 2-oxo-1,2-dihydropyridin-3-yl, wherein said 2-oxo-1,2-dihydropyridin-3-yl may optionally be substituted on the N-atom with a substituent selected from the group consisting of C₁₋₆alkyl; C₃₋₆cycloalkyl; Het^(1a); R¹⁸; R²¹; C₁₋₄alkyl substituted with one, two or three halo atoms; C₁₋₄alkyl substituted with one, two or three —OH substituents; C₁₋₄alkyl substituted with one R¹³; C₁₋₄alkyl substituted with one R¹⁸; C₂₋₆alkenyl; and C₂₋₆alkenyl substituted with one R¹³; provided that when Het^(1a) or R¹⁸ are directly attached to the N-atom of the 2-oxo-1,2-dihydropyridin-3-yl, said Het^(1a) or R¹⁸ are attached to the N-atom via a ring carbon atom; and wherein said 2-oxo-1,2-dihydropyridin-3-yl may optionally be substituted on the ring carbon atoms with in total one, two or three substituents each independently selected from the group consisting of halo; cyano; C₁₋₆alkyl; —O—C₁₋₄alkyl; —C(═O)—R¹⁰; —S(═O)₂—C₁₋₄alkyl; —S(═O)(═N—R^(20a))—C₁₋₄alkyl; —O—C₁₋₄alkyl substituted with one, two or three halo atoms; —O—C₁₋₄alkyl-R¹²; C₃₋₆cycloalkyl; —O—C₃₋₆cycloalkyl; Het^(1a); —O-Het^(1b); R¹⁸; R²¹; —P(═O)—(C₁₋₄alkyl)₂; —NH—C(═O)—C₁₋₄alkyl; —NH—C(═O)—Het^(1g); —NR^(17a)R^(17b); C₁₋₄alkyl substituted with one, two or three halo atoms; C₁₋₄alkyl substituted with one, two or three —OH substituents; C₁₋₄alkyl substituted with one R¹³; C₁₋₄alkyl substituted with one R¹⁸; C₂₋₆alkenyl; and C₂₋₆alkenyl substituted with one R¹³; R¹⁰ represents —OH, —O—C₁₋₄alkyl, —NR^(11a)R^(11b) or Het²; R¹⁸ represents a 5-membered aromatic ring containing one, two or three N-atoms; wherein said 5-membered aromatic ring may optionally be substituted with one substituent selected from the group consisting of C₁₋₄alkyl and C₃₋₆cycloalkyl; R²¹ represents 3,6-dihydro-2H-pyran-4-yl or 1,2,3,6-tetrahydro-4-pyridinyl, wherein 1,2,3,6-tetrahydro-4-pyridinyl may optionally be substituted on the N-atom with C₁₋₄alkyl or C₃₋₆cycloalkyl; Het^(1a), Het^(1c) and Het^(1d) each independently represents a 4- to 7-membered monocyclic saturated heterocyclyl containing one or two heteroatoms each independently selected from O, S, S(═O)_(p) and N; or a 6- to 11-membered bicyclic saturated heterocyclyl, including fused, spiro and bridged cycles, containing one, two or three heteroatoms each independently selected from O, S, S(═O)_(p) and N; wherein said 4- to 7-membered monocyclic saturated heterocyclyl or said 6- to 11-membered bicyclic saturated heterocyclyl may optionally be substituted, where possible, on one, two or three ring N-atoms with a substituent each independently selected from the group consisting of C₁₋₄alkyl, C₃₋₆cycloalkyl, and C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —O—C₁₋₄alkyl; and wherein said 4- to 7-membered monocyclic saturated heterocyclyl or said 6- to 11-membered bicyclic saturated heterocyclyl may optionally be substituted on one, two or three ring C-atoms with one or two substituents each independently selected from the group consisting of —OH, halo, C₁₋₄alkyl, cyano, —C(═O)—C₁₋₄alkyl, —O—C₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)₂; Het^(1b), Het^(1e), Het^(1g) and Het⁴ each independently represents a 4- to 7-membered monocyclic saturated heterocyclyl, attached to the remainder of the molecule of Formula (I) through any available ring carbon atom, said Het^(1b), Het^(1e), Het^(1g) and Het⁴ containing one or two heteroatoms each independently selected from O, S, S(═O)_(p) and N; wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted, where possible, on one or two ring N-atoms with a substituent each independently selected from the group consisting of C₁₋₄alkyl, C₃₋₆cycloalkyl, and C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —O—C₁₋₄alkyl; and wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted on one, two or three ring C-atoms with one or two substituents each independently selected from the group consisting of —OH, halo, C₁₋₄alkyl, cyano, —C(═O)—C₁₋₄alkyl, —O—C₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)₂; Het² represents a heterocyclyl of formula (b-1):

(b-1) represents a N-linked 4- to 7-membered monocyclic saturated heterocyclyl optionally containing one additional heteroatom selected from O, S, S(═O)_(p) and N, or a N-linked 6- to 11-membered bicyclic saturated heterocyclyl, including fused, spiro and bridged cycles, optionally containing one or two additional heteroatoms each independently selected from O, S, S(═O)_(p) and N; wherein in case (b-1) contains one or two additional N-atoms, said one or two N-atoms may optionally be substituted with C₁₋₄alkyl; and wherein (b-1) may optionally be substituted on one, two or three ring C-atoms with one or two substituents each independently selected from the group consisting of halo, —OH, cyano, C₁₋₄alkyl, —O—C₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, and C₁₋₄alkyl-OH; R^(11b) represents hydrogen; Het^(1e); C₁₋₄alkyl; —C₁₋₄alkyl-Het⁵; C₁₋₄alkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, —OH and —O—C₁₋₄alkyl; C₃₋₆cycloalkyl; or C₃₋₆cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, —OH and —O—C₁₋₄alkyl; R¹³ represents —O—C₁₋₄alkyl, —C(═O)NR^(15a)R^(15b), —NR^(19a)R^(19b), C₃₋₆cycloalkyl, Het^(1d), or —C(═O)—Het^(1f); R¹² represents —OH, —O—C₁₋₄alkyl, —NR^(14a)R^(14b), —C(═O)NR^(14c)R^(14d), —S(═O)₂—C₁₋₄alkyl, —S(═O)(═N—R^(20b))—C₁₋₄alkyl, C₃₋₆cycloalkyl, Ar², or Het^(1c); Ar¹ represents phenyl optionally substituted with one hydroxy; Ar² represents phenyl optionally substituted with one C₁₋₄alkyl; Het^(3a), Het^(3b), Het⁵, Het⁶ and Het^(1f) each independently represents a heterocyclyl of formula (c-1):

(c-1) represents a N-linked 4- to 7-membered monocyclic saturated heterocyclyl optionally containing one additional heteroatom selected from O, S, S(═O)_(p) and N; wherein in case (c-1) contains one additional N-atom, said additional N-atom may optionally be substituted with C₁₋₄alkyl or C₃₋₆cycloalkyl; and wherein (c-1) may optionally be substituted on one or two ring C-atoms atoms with one or two substituents each independently selected from the group consisting of halo, C₁₋₄alkyl, and C₃₋₆cycloalkyl; R^(11a), R^(14a), R^(14c), R^(15a), R^(17a) and R^(19a) each independently represents hydrogen or C₁₋₄alkyl; R^(14b), R^(14d), R^(15b), R^(17b) and R^(19b) each independently represents hydrogen; C₁₋₄alkyl; C₃₋₆cycloalkyl; or C₁₋₄alkyl substituted with one substituent selected from the group consisting of halo, —OH and —O—C₁₋₄alkyl; R^(20a) and R^(20b) each independently represents hydrogen; C₁₋₄alkyl; C₃₋₆cycloalkyl; or C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —O—C₁₋₄alkyl; p represents 1 or 2; and the pharmaceutically acceptable addition salts, and the solvates thereof.

The present invention relates in particular to compounds of Formula (I) as defined herein, tautomers and stereoisomeric forms thereof, wherein

R¹ represents C₁₋₄alkyl;

R² represents C₁₋₆alkyl, or C₁₋₆alkyl substituted with one R⁵;

Y represents CR⁴;

R⁴ represents hydrogen or halo;

R⁵ represents Het^(3a), —NR^(6a)R^(6b), or —OR⁷;

R^(6a) represents hydrogen or C₁₋₄alkyl;

R^(6b) represents hydrogen; C₁₋₄alkyl; C₃₋₆cycloalkyl; —C(═O)—C₁₋₄alkyl; —C(═O)—Het⁴; —S(═O)₂—C₁₋₄alkyl; —C(═O)—C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —NR^(16a)R^(16b); or C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —S(═O)₂—C₁₋₄alkyl; R⁷ represents hydrogen, C₁₋₄alkyl, —C₁₋₄alkyl-NR^(8a)R^(8b), —C(═O)—R⁹, —S(═O)₂—OH, —P(═O)₂—OH, —(C═O)—CH(NH₂)—C₁₋₄alkyl-Ar¹, or —C₁₋₄alkyl-Het^(3b); R^(8a) represents hydrogen or C₁₋₄alkyl; R^(8b) represents hydrogen, C₁₋₄alkyl, or C₃₋₆cycloalkyl; R⁹ represents C₁₋₆alkyl, or C₁₋₆alkyl substituted with one substituent selected from the group consisting of —NH₂, —COOH, and Het⁶; R^(16a) and R^(16b) each independently represents hydrogen, C₁₋₄alkyl or C₃₋₆cycloalkyl; R³ represents a 6-membered heteroaromatic ring containing 1 or 2 N-atoms, optionally substituted with one, two or three substituents each independently selected from the group consisting of halo; cyano; C₁₋₆alkyl; —O—C₁₋₄alkyl; —C(═O)—R¹⁰; —S(═O)₂—C₁₋₄alkyl; —S(═O)(═N—R^(20a))—C₁₋₄alkyl; —O—C₁₋₄alkyl substituted with one, two or three halo atoms; —O—C₁₋₄alkyl-R¹²; C₃₋₆cycloalkyl; —O—C₃₋₆cycloalkyl; Het^(1a); —O-Het^(1b); R¹⁸; R²¹; —P(═O)—(C₁₋₄alkyl)₂; —NH—C(═O)—C₁₋₄alkyl; —NH—C(═O)—Het^(1g); —NR^(17a)R^(17b); C₁₋₄alkyl substituted with one, two or three halo atoms; C₁₋₄alkyl substituted with one, two or three —OH substituents; C₁₋₄alkyl substituted with one R¹³; C₁₋₄alkyl substituted with one R¹⁸; C₂₋₆alkenyl; and C₂₋₆alkenyl substituted with one R¹³; R¹⁰ represents —OH, —O—C₁₋₄alkyl, —NR 11^(a)R^(1b) or Het²; R¹⁸ represents a 5-membered aromatic ring containing one, two or three N-atoms; wherein said 5-membered aromatic ring may optionally be substituted with one substituent selected from the group consisting of C₁₋₄alkyl and C₃₋₆cycloalkyl; R²¹ represents 3,6-dihydro-2H-pyran-4-yl or 1,2,3,6-tetrahydro-4-pyridinyl, wherein 1,2,3,6-tetrahydro-4-pyridinyl may optionally be substituted on the N-atom with C₁₋₄alkyl or C₃₋₆cycloalkyl; Het^(1a), Het^(1c) and Het^(1d) each independently represents a 4- to 7-membered monocyclic saturated heterocyclyl containing one or two heteroatoms each independently selected from O, S, S(═O)_(p) and N; or a 6- to 11-membered bicyclic saturated heterocyclyl, including fused, spiro and bridged cycles, containing one, two or three heteroatoms each independently selected from O, S, S(═O)_(p) and N; wherein said 4- to 7-membered monocyclic saturated heterocyclyl or said 6- to 11-membered bicyclic saturated heterocyclyl may optionally be substituted, where possible, on one, two or three ring N-atoms with a substituent each independently selected from the group consisting of C₁₋₄alkyl, C₃₋₆cycloalkyl, and C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —O—C₁₋₄alkyl; and wherein said 4- to 7-membered monocyclic saturated heterocyclyl or said 6- to 11-membered bicyclic saturated heterocyclyl may optionally be substituted on one, two or three ring C-atoms with one or two substituents each independently selected from the group consisting of —OH, halo, C₁₋₄alkyl, cyano, —C(═O)—C₁₋₄alkyl, —O—C₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)₂; Het^(1b), Het^(1e), Het^(1g) and Het⁴ each independently represents a 4- to 7-membered monocyclic saturated heterocyclyl, attached to the remainder of the molecule of Formula (I) through any available ring carbon atom, said Het^(1b), Het^(1e), Het^(1g) and Het⁴ containing one or two heteroatoms each independently selected from O, S, S(═O)_(p) and N; wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted, where possible, on one or two ring N-atoms with a substituent each independently selected from the group consisting of C₁₋₄alkyl, C₃₋₆cycloalkyl, and C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —O—C₁₋₄alkyl; and wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted on one, two or three ring C-atoms with one or two substituents each independently selected from the group consisting of —OH, halo, C₁₋₄alkyl, cyano, —C(═O)—C₁₋₄alkyl, —O—C₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)₂; Het² represents a heterocyclyl of formula (b-1):

(b-1) represents a N-linked 4- to 7-membered monocyclic saturated heterocyclyl optionally containing one additional heteroatom selected from O, S, S(═O)_(p) and N, or a N-linked 6- to 11-membered bicyclic saturated heterocyclyl, including fused, spiro and bridged cycles, optionally containing one or two additional heteroatoms each independently selected from O, S, S(═O)_(p) and N; wherein in case (b-1) contains one or two additional N-atoms, said one or two N-atoms may optionally be substituted with C₁₋₄alkyl; and wherein (b-1) may optionally be substituted on one, two or three ring C-atoms with one or two substituents each independently selected from the group consisting of halo, —OH, cyano, C₁₋₄alkyl, —O—C₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, and C₁₋₄alkyl-OH; R^(11b) represents hydrogen; Het^(1e); C₁₋₄alkyl; —C₁₋₄alkyl-Het⁵; C₁₋₄alkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, —OH and —O—C₁₋₄alkyl; C₃₋₆cycloalkyl; or C₃₋₆cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, —OH and —O—C₁₋₄alkyl; R¹³ represents —O—C₁₋₄alkyl, —C(═O)NR^(15a)R^(15b), —NR^(19a)R^(19b), C₃₋₆cycloalkyl, Het^(1d), or —C(═O)—Het^(1f); R¹² represents —OH, —O—C₁₋₄alkyl, —NR^(14a)R^(14b), —C(═O)NR^(14c)R^(14d), —S(═O)₂—C₁₋₄alkyl, —S(═O)(═N—R^(20b))—C₁₋₄alkyl, C₃₋₆cycloalkyl, Ar², or Het^(1c); Ar¹ represents phenyl optionally substituted with one hydroxy; Ar² represents phenyl optionally substituted with one C₁₋₄alkyl; Het^(3a), Het^(3b), Het⁵, Het⁶ and Het^(1f) each independently represents a heterocyclyl of formula (c-1):

(c-1) represents a N-linked 4- to 7-membered monocyclic saturated heterocyclyl optionally containing one additional heteroatom selected from O, S, S(═O)_(p) and N; wherein in case (c-1) contains one additional N-atom, said additional N-atom may optionally be substituted with C₁₋₄alkyl or C₃₋₆cycloalkyl; and wherein (c-1) may optionally be substituted on one or two ring C-atoms atoms with one or two substituents each independently selected from the group consisting of halo, C₁₋₄alkyl, and C₃₋₆cycloalkyl; R^(11a), R^(14a), R^(14c), R^(15a), R^(17a) and R^(19a) each independently represents hydrogen or C₁₋₄alkyl; R^(14b), R^(14d), R^(15b), R^(17b) and R^(19b) each independently represents hydrogen; C₁₋₄alkyl; C₃₋₆cycloalkyl; or C₁₋₄alkyl substituted with one substituent selected from the group consisting of halo, —OH and —O—C₁₋₄alkyl; R^(20a) and R^(20b) each independently represents hydrogen; C₁₋₄alkyl; C₃₋₆cycloalkyl; or C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —O—C₁₋₄alkyl; p represents 1 or 2; and the pharmaceutically acceptable addition salts, and the solvates thereof.

The present invention relates in particular to compounds of Formula (I) as defined herein, tautomers and stereoisomeric forms thereof, wherein

R¹ represents C₁₋₄alkyl;

R² represents C₁₋₆alkyl, or C₁₋₆alkyl substituted with one R⁵;

Y represents CR⁴;

R⁴ represents hydrogen or halo;

R⁵ represents Het^(3a), —NR^(6a)R^(6b), or —OR⁷;

R^(6a) represents hydrogen or C₁₋₄alkyl;

R^(6b) represents hydrogen; C₁₋₄alkyl; C₃₋₆cycloalkyl; —C(═O)—C₁₋₄alkyl;

—S(═O)₂—C₁₋₄alkyl; —C(═O)—C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —NR^(16a)R^(16b); or C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —S(═O)₂—C₁₋₄alkyl;

R⁷ represents hydrogen, C₁₋₄alkyl, —C₁₋₄alkyl-NR^(8a)R^(8b), —C(═O)—R⁹, —S(═O)₂—OH, —P(═O)₂—OH, —(C═O)—CH(NH₂)—C₁₋₄alkyl-Ar¹, or —C₁₋₄alkyl-Het^(3b);

R^(8a) represents hydrogen or C₁₋₄alkyl;

R^(8b) represents hydrogen, C₁₋₄alkyl, or C₃₋₆cycloalkyl;

R⁹ represents C₁₋₄alkyl, or C₁₋₄alkyl substituted with one substituent selected from the group consisting of —NH₂, —COOH, and Het⁶;

R^(16a) and R^(16b) each independently represents hydrogen, C₁₋₄alkyl or C₃₋₆cycloalkyl;

R³ represents a 6-membered heteroaromatic ring containing 1 or 2 N-atoms, optionally substituted with one, two or three substituents each independently selected from the group consisting of halo; cyano; C₁₋₆alkyl; —O—C₁₋₄alkyl; —C(═O)—R¹⁰; —S(═O)₂—C₁₋₄alkyl; —S(═O)(═N—R^(20a))—C₁₋₄alkyl; —O—C₁₋₄alkyl substituted with one, two or three halo atoms; —O—C₁₋₄alkyl-R¹²; C₃₋₆cycloalkyl; —O—C₃₋₆cycloalkyl; Het^(1a); —O-Het^(1b); R¹⁸; R²¹; —P(═O)—(C₁₋₄alkyl)₂; —NH—C(═O)—C₁₋₄alkyl; —NH—C(═O)—Het^(1g); —NR^(17a)R^(17b); C₁₋₄alkyl substituted with one, two or three halo atoms; C₁₋₄alkyl substituted with one, two or three —OH substituents; C₁₋₄alkyl substituted with one R¹³; C₁₋₄alkyl substituted with one R¹⁸; C₂₋₆alkenyl; and C₂₋₆alkenyl substituted with one R¹³; R¹⁰ represents —OH, —O—C₁₋₄alkyl, —NR^(11a)R^(11b) or Het²; R¹⁸ represents a 5-membered aromatic ring containing one, two or three N-atoms; wherein said 5-membered aromatic ring may optionally be substituted with one substituent selected from the group consisting of C₁₋₄alkyl and C₃₋₆cycloalkyl; R²¹ represents 3,6-dihydro-2H-pyran-4-yl or 1,2,3,6-tetrahydro-4-pyridinyl, wherein 1,2,3,6-tetrahydro-4-pyridinyl may optionally be substituted on the N-atom with C₁₋₄alkyl or C₃₋₆cycloalkyl; Het^(1a), Het^(1c) and Het^(1d) each independently represents a 4- to 7-membered monocyclic saturated heterocyclyl containing one or two heteroatoms each independently selected from O, S, S(═O)_(p) and N; wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted, where possible, on one or two ring N-atoms with a substituent each independently selected from the group consisting of C₁₋₄alkyl, C₃₋₆cycloalkyl, and C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —O—C₁₋₄alkyl; and wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted on one, two or three ring C-atoms with one or two substituents each independently selected from the group consisting of —OH, halo, C₁₋₄alkyl, cyano, —C(═O)—C₁₋₄alkyl, —O—C₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)₂; Het^(1b), Het^(1e), and Het^(1g) each independently represents a 4- to 7-membered monocyclic saturated heterocyclyl, attached to the remainder of the molecule of Formula (I) through any available ring carbon atom, said Het^(1b), Het^(1e), and Het^(1g) containing one or two heteroatoms each independently selected from O, S, S(═O)_(p) and N; wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted, where possible, on one or two ring N-atoms with a substituent each independently selected from the group consisting of C₁₋₄alkyl, C₃₋₆cycloalkyl, and C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —O—C₁₋₄alkyl; and wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted on one, two or three ring C-atoms with one or two substituents each independently selected from the group consisting of —OH, halo, C₁₋₄alkyl, cyano, —C(═O)—C₁₋₄alkyl, —O—C₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)₂; Het² represents a heterocyclyl of formula (b-1):

(b-1) represents a N-linked 4- to 7-membered monocyclic saturated heterocyclyl optionally containing one additional heteroatom selected from O, S, S(═O)_(p) and N, or a N-linked 6- to 11-membered bicyclic saturated heterocyclyl, including fused, spiro and bridged cycles, optionally containing one or two additional heteroatoms each independently selected from O, S, S(═O)_(p) and N; wherein in case (b-1) contains one or two additional N-atoms, said one or two N-atoms may optionally be substituted with C₁₋₄alkyl; and wherein (b-1) may optionally be substituted on one, two or three ring C-atoms with one or two substituents each independently selected from the group consisting of halo, —OH, cyano, C₁₋₄alkyl, —O—C₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, and C₁₋₄alkyl-OH; R^(11b) represents hydrogen; Het^(1e); C₁₋₄alkyl; —C₁₋₄alkyl-Het⁵; C₁₋₄alkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, —OH and —O—C₁₋₄alkyl; C₃₋₆cycloalkyl; or C₃₋₆cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, —OH and —O—C₁₋₄alkyl; R¹³ represents —O—C₁₋₄alkyl, —C(═O)NR^(15a)R^(15b), —NR^(19a)R^(19b), C₃₋₆cycloalkyl, Het^(1d), or —C(═O)—Het^(1f); R¹² represents —OH, —O—C₁₋₄alkyl, —NR^(14a)R^(14b), —C(═O)NR^(14c)R^(14d), —S(═O)₂—C₁₋₄alkyl, —S(═O)(═N—R^(20b))—C₁₋₄alkyl, C₃₋₆cycloalkyl, Ar², or Het^(1c); Ar¹ represents phenyl optionally substituted with one hydroxy; Ar² represents phenyl optionally substituted with one C₁₋₄alkyl; Het^(3a), Het^(3b), Het⁵, Het⁶ and Het^(1f) each independently represents a heterocyclyl of formula (c-1):

(c-1) represents a N-linked 4- to 7-membered monocyclic saturated heterocyclyl optionally containing one additional heteroatom selected from O, S, S(═O)_(p) and N; wherein in case (c-1) contains one additional N-atom, said additional N-atom may optionally be substituted with C₁₋₄alkyl or C₃₋₆cycloalkyl; and wherein (c-1) may optionally be substituted on one or two ring C-atoms atoms with one or two substituents each independently selected from the group consisting of halo, C₁₋₄alkyl, and C₃₋₆cycloalkyl; R^(11a), R^(14a), R^(14c), R^(15a), R^(17a) and R^(19a) each independently represents hydrogen or C₁₋₄alkyl; R^(14b), R^(14d), R^(15b), R^(17b) and R^(19b) each independently represents hydrogen; C₁₋₄alkyl; C₃₋₆cycloalkyl; or C₁₋₄alkyl substituted with one substituent selected from the group consisting of halo, —OH and —O—C₁₋₄alkyl; R^(20a) and R^(20b) each independently represents hydrogen; C₁₋₄alkyl; C₃₋₆cycloalkyl; or C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —O—C₁₋₄alkyl; p represents 1 or 2; and the pharmaceutically acceptable addition salts, and the solvates thereof.

The present invention relates in particular to compounds of Formula (I) as defined herein, tautomers and stereoisomeric forms thereof, wherein

R¹ represents C₁₋₄alkyl;

R² represents C₁₋₆alkyl, or C₁₋₆alkyl substituted with one R⁵;

Y represents CR⁴;

R⁴ represents hydrogen or halo;

R⁵ represents Het^(3a), —NR^(6a)R^(6b), or —OR⁷;

R^(6a) represents hydrogen or C₁₋₄alkyl;

R^(6b) represents hydrogen; C₁₋₄alkyl; C₃₋₆cycloalkyl; —C(═O)—C₁₋₄alkyl;

—S(═O)₂—C₁₋₄alkyl; —C(═O)—C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —NR^(16a)R^(16b); or C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —S(═O)₂—C₁₋₄alkyl;

R⁷ represents hydrogen, C₁₋₄alkyl, —C₁₋₄alkyl-NR^(8a)R^(8b), —C(═O)—R⁹, —S(═O)₂—OH, —P(═O)₂—OH, —(C═O)—CH(NH₂)—C₁₋₄alkyl-Ar¹, or —C₁₋₄alkyl-Het^(3b);

R^(8a) represents hydrogen or C₁₋₄alkyl;

R^(8b) represents hydrogen, C₁₋₄alkyl, or C₃₋₆cycloalkyl;

R⁹ represents C₁₋₄alkyl, or C₁₋₄alkyl substituted with one substituent selected from the group consisting of —NH₂, —COOH, and Het⁶;

R^(16a) and R^(16b) each independently represents hydrogen, C₁₋₄alkyl or C₃₋₆cycloalkyl;

R³ represents 2-oxo-1,2-dihydropyridin-3-yl,

wherein said 2-oxo-1,2-dihydropyridin-3-yl may optionally be substituted on the N-atom with a substituent selected from the group consisting of C₁₋₆alkyl; C₃₋₆cycloalkyl; Het^(1a); R¹⁸; R²¹; C₁₋₄alkyl substituted with one, two or three halo atoms; C₁₋₄alkyl substituted with one, two or three —OH substituents; C₁₋₄alkyl substituted with one R¹³; C₁₋₄alkyl substituted with one R¹⁸; C₂₋₆alkenyl; and C₂₋₆alkenyl substituted with one R¹³; provided that when Het^(1a) or R¹⁸ are directly attached to the N-atom of the 2-oxo-1,2-dihydropyridin-3-yl, said Het^(1a) or R¹⁸ are attached to the N-atom via a ring carbon atom; and wherein said 2-oxo-1,2-dihydropyridin-3-yl may optionally be substituted on the ring carbon atoms with in total one, two or three substituents each independently selected from the group consisting of halo; cyano; C₁₋₆alkyl; —O—C₁₋₄alkyl; —C(═O)—R¹⁰; —S(═O)₂—C₁₋₄alkyl; —S(═O)(═N—R^(20a))—C₁₋₄alkyl; —O—C₁₋₄alkyl substituted with one, two or three halo atoms; —O—C₁₋₄alkyl-R¹²; C₃₋₆cycloalkyl; —O—C₃₋₆cycloalkyl; Het^(1a); —O-Het^(1b); R¹⁸; R²¹; —P(═O)—(C₁₋₄alkyl)₂; —NH—C(═O)—C₁₋₄alkyl; —NH—C(═O)—Het^(1g); —NR^(17a)R^(17b); C₁₋₄alkyl substituted with one, two or three halo atoms; C₁₋₄alkyl substituted with one, two or three —OH substituents; C₁₋₄alkyl substituted with one R¹³; C₁₋₄alkyl substituted with one R¹⁸; C₂₋₆alkenyl; and C₂₋₆alkenyl substituted with one R¹³; R¹⁰ represents —OH, —O—C₁₋₄alkyl, —NR 11^(a)R^(11b) or Het²; R¹⁸ represents a 5-membered aromatic ring containing one, two or three N-atoms; wherein said 5-membered aromatic ring may optionally be substituted with one substituent selected from the group consisting of C₁₋₄alkyl and C₃₋₆cycloalkyl; R²¹ represents 3,6-dihydro-2H-pyran-4-yl or 1,2,3,6-tetrahydro-4-pyridinyl, wherein 1,2,3,6-tetrahydro-4-pyridinyl may optionally be substituted on the N-atom with C₁₋₄alkyl or C₃₋₆cycloalkyl; Het^(1a), Het^(1c) and Het^(1d) each independently represents a 4- to 7-membered monocyclic saturated heterocyclyl containing one or two heteroatoms each independently selected from O, S, S(═O)_(p) and N; wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted, where possible, on one or two ring N-atoms with a substituent each independently selected from the group consisting of C₁₋₄alkyl, C₃₋₆cycloalkyl, and C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —O—C₁₋₄alkyl; and wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted on one or two ring C-atoms with one or two substituents each independently selected from the group consisting of —OH, halo, C₁₋₄alkyl, cyano, —C(═O)—C₁₋₄alkyl, —O—C₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)₂; Het^(1b), Het^(1e) and Het^(1g) each independently represents a 4- to 7-membered monocyclic saturated heterocyclyl, attached to the remainder of the molecule of Formula (I) through any available ring carbon atom, said Het^(1b), Het^(1e) and Het^(1g) containing one or two heteroatoms each independently selected from O, S, S(═O)_(p) and N; wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted, where possible, on one or two ring N-atoms with a substituent each independently selected from the group consisting of C₁₋₄alkyl, C₃₋₆cycloalkyl, and C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —O—C₁₋₄alkyl; and wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted on one, two or three ring C-atoms with one or two substituents each independently selected from the group consisting of —OH, halo, C₁₋₄alkyl, cyano, —C(═O)—C₁₋₄alkyl, —O—C₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)₂; Het² represents a heterocyclyl of formula (b-1):

(b-1) represents a N-linked 4- to 7-membered monocyclic saturated heterocyclyl optionally containing one additional heteroatom selected from O, S, S(═O)_(p) and N, or a N-linked 6- to 11-membered bicyclic saturated heterocyclyl, including fused, spiro and bridged cycles, optionally containing one or two additional heteroatoms each independently selected from O, S, S(═O)_(p) and N; wherein in case (b-1) contains one or two additional N-atoms, said one or two N-atoms may optionally be substituted with C₁₋₄alkyl; and wherein (b-1) may optionally be substituted on one, two or three ring C-atoms with one or two substituents each independently selected from the group consisting of halo, —OH, cyano, C₁₋₄alkyl, —O—C₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, and C₁₋₄alkyl-OH; R^(11b) represents hydrogen; Het^(1e); C₁₋₄alkyl; —C₁₋₄alkyl-Het⁵; C₁₋₄alkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, —OH and —O—C₁₋₄alkyl; C₃₋₆cycloalkyl; or C₃₋₆cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, —OH and —O—C₁₋₄alkyl; R¹³ represents —O—C₁₋₄alkyl, —C(═O)NR^(15a)R^(15b), —NR^(19a)R^(19b), C₃₋₆cycloalkyl, Het^(1d), or —C(═O)—Het^(1f); R¹² represents —OH, —O—C₁₋₄alkyl, —NR^(14a)R^(14b), —C(═O)NR^(14c)R^(14d), —S(═O)₂—C₁₋₄alkyl, —S(═O)(═N—R^(2b))—C₁₋₄alkyl, C₃₋₆cycloalkyl, Ar², or Het^(1c); Ar¹ represents phenyl optionally substituted with one hydroxy; Ar² represents phenyl optionally substituted with one C₁₋₄alkyl; Het^(3a), Het^(3b), Het⁵, Het⁶ and Het^(1f) each independently represents a heterocyclyl of formula (c-1):

(c-1) represents a N-linked 4- to 7-membered monocyclic saturated heterocyclyl optionally containing one additional heteroatom selected from O, S, S(═O)_(p) and N; wherein in case (c-1) contains one additional N-atom, said additional N-atom may optionally be substituted with C₁₋₄alkyl or C₃₋₆cycloalkyl; and wherein (c-1) may optionally be substituted on one or two ring C-atoms atoms with one or two substituents each independently selected from the group consisting of halo, C₁₋₄alkyl, and C₃₋₆cycloalkyl; R^(11a), R^(14a), R^(14c), R^(15a), R^(17a) and R^(19a) each independently represents hydrogen or C₁₋₄alkyl; R^(14b), R^(14d), R^(15b), R^(17b) and R^(19b) each independently represents hydrogen; C₁₋₄alkyl; C₃₋₆cycloalkyl; or C₁₋₄alkyl substituted with one substituent selected from the group consisting of halo, —OH and —O—C₁₋₄alkyl; R^(20a) and R^(20b) each independently represents hydrogen; C₁₋₄alkyl; C₃₋₆cycloalkyl; or C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —O—C₁₋₄alkyl; p represents 1 or 2; and the pharmaceutically acceptable addition salts, and the solvates thereof.

The present invention relates in particular to compounds of Formula (I) as defined herein, tautomers and stereoisomeric forms thereof, wherein

R¹ represents C₁₋₄alkyl;

R² represents C₁₋₆alkyl, or C₁₋₆alkyl substituted with one R⁵;

Y represents CR⁴ or N;

R⁴ represents hydrogen or halo;

R⁵ represents halo, Het^(3a), —NR^(6a)R^(6b), or —OR⁷;

R^(6a) represents hydrogen or C₁₋₄alkyl;

R^(6b) represents hydrogen; C₁₋₄alkyl; C₃₋₆cycloalkyl; —C(═O)—C₁₋₄alkyl; —C(═O)—Het⁴; —S(═O)₂—C₁₋₄alkyl; —C(═O)—C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —NR^(6a)R^(16b); or C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —S(═O)₂—C₁₋₄alkyl; R⁷ represents hydrogen, C₁₋₄alkyl, —C₁₋₄alkyl-NR^(8a)R^(8b), —C(═O)—R⁹, —S(═O)₂—OH, —P(═O)₂—OH, —(C═O)—CH(NH₂)—C₁₋₄alkyl-Ar¹, or —C₁₋₄alkyl-Het^(3b); R^(8a) represents hydrogen or C₁₋₄alkyl; R^(8b) represents hydrogen, C₁₋₄alkyl, or C₃₋₆cycloalkyl; R⁹ represents C₁₋₄alkyl, or C₁₋₄alkyl substituted with one substituent selected from the group consisting of —NH₂, —COOH, and Het⁶; R^(16a) and R^(16b) each independently represents hydrogen, C₁₋₄alkyl or C₃₋₆cycloalkyl; R³ represents a 6-membered heteroaromatic ring containing 1 or 2 N-atoms, optionally substituted with one, two or three substituents each independently selected from the group consisting of halo; cyano; C₁₋₆alkyl; —O—C₁₋₄alkyl; —C(═O)—R¹⁰; —S(═O)₂—C₁₋₄alkyl; —S(═O)(═N—R^(20a))—C₁₋₄alkyl; —O—C₁₋₄alkyl substituted with one, two or three halo atoms; —O—C₁₋₄alkyl-R¹²; C₃₋₆cycloalkyl; —O—C₃₋₆cycloalkyl; Het^(1a); —O-Het^(1b); R¹⁸; R²¹; —P(═O)—(C₁₋₄alkyl)₂; —NH—C(═O)—C₁₋₄alkyl; —NH—C(═O)—Het^(1g); —NR^(17a)R^(17b); C₁₋₄alkyl substituted with one, two or three halo atoms; C₁₋₄alkyl substituted with one, two or three —OH substituents; C₁₋₄alkyl substituted with one R¹³; C₁₋₄alkyl substituted with one R¹⁸; C₂₋₆alkenyl; C₂₋₆alkenyl substituted with one R¹³; C₂₋₆alkynyl; and C₂₋₆alkynyl substituted with one R¹³; or R³ represents 2-oxo-1,2-dihydropyridin-3-yl, wherein said 2-oxo-1,2-dihydropyridin-3-yl may optionally be substituted on the N-atom with a substituent selected from the group consisting of C₁₋₆alkyl; C₃₋₆cycloalkyl; Het^(1a); R¹⁸; R²¹; C₁₋₄alkyl substituted with one, two or three halo atoms; C₁₋₄alkyl substituted with one, two or three —OH substituents; C₁₋₄alkyl substituted with one R¹³; C₁₋₄alkyl substituted with one R¹⁸; C₂₋₆alkenyl; and C₂₋₆alkenyl substituted with one R¹³; provided that when Het^(1a) or R¹⁸ are directly attached to the N-atom of the 2-oxo-1,2-dihydropyridin-3-yl, said Het^(1a) or R¹⁸ are attached to the N-atom via a ring carbon atom; and wherein said 2-oxo-1,2-dihydropyridin-3-yl may optionally be substituted on the ring carbon atoms with in total one, two or three substituents each independently selected from the group consisting of halo; cyano; C₁₋₆alkyl; —O—C₁₋₄alkyl; —C(═O)—R¹⁰; —S(═O)₂—C₁₋₄alkyl; —S(═O)(═N—R^(20a))—C₁₋₄alkyl; —O—C₁₋₄alkyl substituted with one, two or three halo atoms; —O—C₁₋₄alkyl-R¹²; C₃₋₆cycloalkyl; —O—C₃₋₆cycloalkyl; Het^(1a); —O-Het^(1b); R¹⁸; R²¹; —P(═O)—(C₁₋₄alkyl)₂; —NH—C(═O)—C₁₋₄alkyl; —NH—C(═O)—Het¹; —NR^(17a)R^(17b); C₁₋₄alkyl substituted with one, two or three halo atoms; C₁₋₄alkyl substituted with one, two or three —OH substituents; C₁₋₄alkyl substituted with one R¹³; C₁₋₄alkyl substituted with one R¹⁸; C₂₋₆alkenyl; C₂₋₆alkenyl substituted with one R¹³; C₂₋₆alkynyl; and C₂₋₆alkynyl substituted with one R¹³; R¹⁰ represents —OH, —O—C₁₋₄alkyl, —NR^(11a)R^(11b) or Het²; R¹⁸ represents a 5-membered aromatic ring containing one, two or three N-atoms; wherein said 5-membered aromatic ring may optionally be substituted with one substituent selected from the group consisting of C₁₋₄alkyl and C₃₋₆cycloalkyl; R²¹ represents 3,6-dihydro-2H-pyran-4-yl or 1,2,3,6-tetrahydro-4-pyridinyl, wherein 1,2,3,6-tetrahydro-4-pyridinyl may optionally be substituted on the N-atom with C₁₋₄alkyl or C₃₋₆cycloalkyl; Het^(1a), Het^(1c) and Het^(1d) each independently represents a 4- to 7-membered monocyclic saturated heterocyclyl containing one or two heteroatoms each independently selected from O, S, S(═O)_(p) and N; or a 6- to 11-membered bicyclic saturated heterocyclyl, including fused, spiro and bridged cycles, containing one, two or three heteroatoms each independently selected from O, S, S(═O)_(p) and N; wherein said 4- to 7-membered monocyclic saturated heterocyclyl or said 6- to 11-membered bicyclic saturated heterocyclyl may optionally be substituted, where possible, on one, two or three ring N-atoms with a substituent each independently selected from the group consisting of C₁₋₄alkyl, C₃₋₆cycloalkyl, and C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —O—C₁₋₄alkyl; and wherein said 4- to 7-membered monocyclic saturated heterocyclyl or said 6- to 11-membered bicyclic saturated heterocyclyl may optionally be substituted on one, two or three ring C-atoms with one substituent each independently selected from the group consisting of —OH, halo, C₁₋₄alkyl, cyano, —C(═O)—C₁₋₄alkyl, —O—C₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)₂; Het^(1b), Het^(1e), Het^(1g), Het⁴, Het⁷ and Het⁸ each independently represents a 4- to 7-membered monocyclic saturated heterocyclyl, attached to the remainder of the molecule of Formula (I) through any available ring carbon atom, said Het^(1b), Het^(1e), Het^(1g), Het⁴, Het⁷ and Het⁸ containing one or two heteroatoms each independently selected from O, S, S(═O)_(p) and N; wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted, where possible, on one or two ring N-atoms with a substituent each independently selected from the group consisting of C₁₋₄alkyl, C₃₋₆cycloalkyl, and C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —O—C₁₋₄alkyl; and wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted on one, two or three ring C-atoms with one substituent each independently selected from the group consisting of —OH, halo, C₁₋₄alkyl, cyano, —C(═O)—C₁₋₄alkyl, —O—C₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)₂; Het² represents a heterocyclyl of formula (b-1):

(b-1) represents a N-linked 4- to 7-membered monocyclic saturated heterocyclyl optionally containing one additional heteroatom selected from O, S, S(═O)_(p) and N, or a N-linked 6- to 11-membered bicyclic saturated heterocyclyl, including fused, spiro and bridged cycles, optionally containing one or two additional heteroatoms each independently selected from O, S, S(═O)_(p) and N; wherein in case (b-1) contains one or two additional N-atoms, said one or two N-atoms may optionally be substituted with a substituent each independently selected from the group consisting of C₁₋₄alkyl, C₃₋₆cycloalkyl and Het⁷; and wherein (b-1) may optionally be substituted on one, two or three ring C-atoms with one substituent each independently selected from the group consisting of halo, —OH, cyano, C₁₋₄alkyl, —O—C₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, and C₁₋₄alkyl-OH;

-   -   R^(11b) represents hydrogen; Het^(1e); C₁₋₄alkyl;         —C₁₋₄alkyl-Het⁵; —C₁₋₄alkyl-Het⁸; C₁₋₄alkyl substituted with         one, two or three substituents each independently selected from         the group consisting of halo, —OH and —O—C₁₋₄alkyl;         C₃₋₆cycloalkyl; or C₃₋₆cycloalkyl substituted with one, two or         three substituents each independently selected from the group         consisting of halo,         —OH and —O—C₁₋₄alkyl;         R¹³ represents —O—C₁₋₄alkyl, —C(═O)NR^(15a)R^(15b),         —NR^(19a)R^(19b), C₃₋₆cycloalkyl, Het^(1d), or —C(═O)—Het^(1f);         R¹² represents —OH, —O—C₁₋₄alkyl, —NR^(14a)R^(14b),         —C(═O)NR^(14c)R^(14d), —S(═O)₂—C₁₋₄alkyl,         —S(═O)(═N—R^(20b))—C₁₋₄alkyl, C₃₋₆cycloalkyl, Ar², or Het^(1c);         Ar¹ represents phenyl optionally substituted with one hydroxy;         Ar² represents phenyl optionally substituted with one C₁₋₄alkyl;         Het^(3a), Het^(3b), Het⁵, Het⁶ and Het^(1f) each independently         represents a heterocyclyl of formula (c-1):

(c-1) represents a N-linked 4- to 7-membered monocyclic saturated heterocyclyl optionally containing one additional heteroatom selected from O, S, S(═O)_(p) and N; wherein in case (c-1) contains one additional N-atom, said additional N-atom may optionally be substituted with C₁₋₄alkyl or C₃₋₆cycloalkyl; and wherein (c-1) may optionally be substituted on one or two ring C-atoms atoms with one substituent each independently selected from the group consisting of halo, C₁₋₄alkyl, and C₃₋₆cycloalkyl; R^(11a), R^(14a), R^(14c), R^(15a), R^(17a) and R^(19a) each independently represents hydrogen or C₁₋₄alkyl; R^(14b), R^(14d), R^(15b), R^(17b) and R^(19b) each independently represents hydrogen; C₁₋₄alkyl; C₃₋₆cycloalkyl; —C(═O)—C₁₋₄alkyl; C₁₋₄alkyl substituted with one substituent selected from the group consisting of halo, —OH and —O—C₁₋₄alkyl; —C(═O)—C₁₋₄alkyl substituted with one substituent selected from the group consisting of halo, —OH and —O—C₁₋₄alkyl; or —S(═O)₂—C₁₋₄alkyl; R^(20a) and R^(20b) each independently represents hydrogen; C₁₋₄alkyl; C₃₋₆cycloalkyl; or C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —O—C₁₋₄alkyl; p represents 1 or 2; and the pharmaceutically acceptable addition salts, and the solvates thereof.

The present invention relates in particular to compounds of Formula (I) as defined herein, tautomers and stereoisomeric forms thereof, wherein

R¹ represents C₁₋₄alkyl;

R² represents C₁₋₆alkyl, or C₁₋₆alkyl substituted with one R⁵;

Y represents CR⁴;

R⁴ represents hydrogen or halo;

R⁵ represents Het^(3a), —NR^(6a)R^(6b), or —OR⁷;

R^(6a) represents hydrogen or C₁₋₄alkyl;

R^(6b) represents hydrogen; C₁₋₄alkyl; C₃₋₆cycloalkyl; —C(═O)—C₁₋₄alkyl; —C(═O)—Het⁴; —S(═O)₂—C₁₋₄alkyl; —C(═O)—C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —NR^(16a)R^(16b); or C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —S(═O)₂—C₁₋₄alkyl; R⁷ represents hydrogen, C₁₋₄alkyl, —C₁₋₄alkyl-NR^(8a)R^(8b), —C(═O)—R⁹, —S(═O)₂—OH, —P(═O)₂—OH, —(C═O)—CH(NH₂)—C₁₋₄alkyl-Ar¹, or —C₁₋₄alkyl-Het^(3b); R^(8a) represents hydrogen or C₁₋₄alkyl; R^(8b) represents hydrogen, C₁₋₄alkyl, or C₃₋₆cycloalkyl; R⁹ represents C₁₋₄alkyl, or C₁₋₄alkyl substituted with one substituent selected from the group consisting of —NH₂, —COOH, and Het⁶; R^(16a) and R^(16b) each independently represents hydrogen, C₁₋₄alkyl or C₃₋₆cycloalkyl; R³ represents a 6-membered heteroaromatic ring containing 1 or 2 N-atoms, optionally substituted with one, two or three substituents each independently selected from the group consisting of halo; cyano; C₁₋₆alkyl; —O—C₁₋₄alkyl; —C(═O)—R¹⁰; —S(═O)₂—C₁₋₄alkyl; —S(═O)(═N—R^(20a))—C₁₋₄alkyl; —O—C₁₋₄alkyl substituted with one, two or three halo atoms; —O—C₁₋₄alkyl-R¹²; C₃₋₆cycloalkyl; —O—C₃₋₆cycloalkyl; Het^(1a); —O-Het^(1b); R¹⁸; R²¹; —P(═O)—(C₁₋₄alkyl)₂; —NH—C(═O)—C₁₋₄alkyl; —NH—C(═O)—Het^(1g); —NR^(17a)R^(17b); C₁₋₄alkyl substituted with one, two or three halo atoms; C₁₋₄alkyl substituted with one, two or three —OH substituents; C₁₋₄alkyl substituted with one R¹³; C₁₋₄alkyl substituted with one R¹⁸; C₂₋₆alkenyl; and C₂₋₆alkenyl substituted with one R¹³; or R³ represents 2-oxo-1,2-dihydropyridin-3-yl, wherein said 2-oxo-1,2-dihydropyridin-3-yl may optionally be substituted on the N-atom with a substituent selected from the group consisting of C₁₋₆alkyl; C₃₋₆cycloalkyl; Het^(1a); R¹⁸; R²¹; C₁₋₄alkyl substituted with one, two or three halo atoms; C₁₋₄alkyl substituted with one, two or three —OH substituents; C₁₋₄alkyl substituted with one R¹³; C₁₋₄alkyl substituted with one R¹⁸; C₂₋₆alkenyl; and C₂₋₆alkenyl substituted with one R¹³; provided that when Het^(1a) or R¹⁸ are directly attached to the N-atom of the 2-oxo-1,2-dihydropyridin-3-yl, said Het^(1a) or R¹⁸ are attached to the N-atom via a ring carbon atom; and wherein said 2-oxo-1,2-dihydropyridin-3-yl may optionally be substituted on the ring carbon atoms with in total one, two or three substituents each independently selected from the group consisting of halo; cyano; C₁_alkyl; —O—C₁₋₄alkyl; —C(═O)—R¹⁰; —S(═O)₂—C₁₋₄alkyl; —S(═O)(═N—R^(20a))—C₁₋₄alkyl; —O—C₁₋₄alkyl substituted with one, two or three halo atoms; —O—C₁₋₄alkyl-R¹²; C₃₋₆cycloalkyl; —O—C₃₋₆cycloalkyl; Het¹a; —O-Het^(1b); R¹⁸; R²¹; —P(═O)—(C₁₋₄alkyl)₂; —NH—C(═O)—C₁₋₄alkyl; —NH—C(═O)—Het^(1g); —NR^(17a)R^(17b); C₁₋₄alkyl substituted with one, two or three halo atoms; C₁₋₄alkyl substituted with one, two or three —OH substituents; C₁₋₄alkyl substituted with one R¹³; C₁₋₄alkyl substituted with one R¹⁸; C₂₋₆alkenyl; and C₂₋₆alkenyl substituted with one R¹³; R¹⁰ represents —OH, —O—C₁₋₄alkyl, —NR^(11a)R^(11b) or Het²; R¹⁸ represents a 5-membered aromatic ring containing one, two or three N-atoms; wherein said 5-membered aromatic ring may optionally be substituted with one substituent selected from the group consisting of C₁₋₄alkyl and C₃₋₆cycloalkyl; R²¹ represents 3,6-dihydro-2H-pyran-4-yl or 1,2,3,6-tetrahydro-4-pyridinyl, wherein 1,2,3,6-tetrahydro-4-pyridinyl may optionally be substituted on the N-atom with C₁₋₄alkyl or C₃₋₆cycloalkyl; Het^(1a), Het^(1c) and Het^(1d) each independently represents a 4- to 7-membered monocyclic saturated heterocyclyl containing one or two heteroatoms each independently selected from O, S, S(═O)_(p) and N; or a 6- to 11-membered bicyclic saturated heterocyclyl, including fused, spiro and bridged cycles, containing one, two or three heteroatoms each independently selected from O, S, S(═O)_(p) and N; wherein said 4- to 7-membered monocyclic saturated heterocyclyl or said 6- to 11-membered bicyclic saturated heterocyclyl may optionally be substituted, where possible, on one, two or three ring N-atoms with a substituent each independently selected from the group consisting of C₁₋₄alkyl, C₃₋₆cycloalkyl, and C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —O—C₁₋₄alkyl; and wherein said 4- to 7-membered monocyclic saturated heterocyclyl or said 6- to 11-membered bicyclic saturated heterocyclyl may optionally be substituted on one, two or three ring C-atoms with one substituent each independently selected from the group consisting of —OH, halo, C₁₋₄alkyl, cyano, —C(═O)—C₁₋₄alkyl, —O—C₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)₂; Het^(1b), Het^(1e), Het^(1g) and Het⁴ each independently represents a 4- to 7-membered monocyclic saturated heterocyclyl, attached to the remainder of the molecule of Formula (I) through any available ring carbon atom, said Het^(1b), Het^(1e), Het^(1g) and Het⁴ containing one or two heteroatoms each independently selected from O, S, S(═O)_(p) and N; wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted, where possible, on one or two ring N-atoms with a substituent each independently selected from the group consisting of C₁₋₄alkyl, C₃₋₆cycloalkyl, and C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —O—C₁₋₄alkyl; and wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted on one, two or three ring C-atoms with one substituent each independently selected from the group consisting of —OH, halo, C₁₋₄alkyl, cyano, —C(═O)—C₁₋₄alkyl, —O—C₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)₂; Het² represents a heterocyclyl of formula (b-1):

(b-1) represents a N-linked 4- to 7-membered monocyclic saturated heterocyclyl optionally containing one additional heteroatom selected from O, S, S(═O)_(p) and N, or a N-linked 6- to 11-membered bicyclic saturated heterocyclyl, including fused, spiro and bridged cycles, optionally containing one or two additional heteroatoms each independently selected from O, S, S(═O)_(p) and N; wherein in case (b-1) contains one or two additional N-atoms, said one or two N-atoms may optionally be substituted with C₁₋₄alkyl; and wherein (b-1) may optionally be substituted on one, two or three ring C-atoms with one substituent each independently selected from the group consisting of halo, —OH, cyano, C₁₋₄alkyl, —O—C₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, and C₁₋₄alkyl-OH; R^(11b) represents hydrogen; Het^(1e); C₁₋₄alkyl; —C₁₋₄alkyl-Het⁵; C₁₋₄alkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, —OH and —O—C₁₋₄alkyl; C₃₋₆cycloalkyl; or C₃₋₆cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, —OH and —O—C₁₋₄alkyl; R¹³ represents —O—C₁₋₄alkyl, —C(═O)NR^(15a)R^(15b), —NR^(19a)R^(19b), C₃₋₆cycloalkyl, Het^(1d), or —C(═O)—Het^(1f); R¹² represents —OH, —O—C₁₋₄alkyl, —NR^(14a)R^(14b), —C(═O)NR^(14c)R^(14d), —S(═O)₂—C₁₋₄alkyl, —S(═O)(═N—R^(20b))—C₁₋₄alkyl, C₃₋₆cycloalkyl, Ar², or Het^(1c); Ar¹ represents phenyl optionally substituted with one hydroxy; Ar² represents phenyl optionally substituted with one C₁₋₄alkyl; Het^(3a), Het^(3b), Het⁵, Het⁶ and Het^(1f) each independently represents a heterocyclyl of formula (c-1):

(c-1) represents a N-linked 4- to 7-membered monocyclic saturated heterocyclyl optionally containing one additional heteroatom selected from O, S, S(═O)_(p) and N; wherein in case (c-1) contains one additional N-atom, said additional N-atom may optionally be substituted with C₁₋₄alkyl or C₃₋₆cycloalkyl; and wherein (c-1) may optionally be substituted on one or two ring C-atoms atoms with one substituent each independently selected from the group consisting of halo, C₁₋₄alkyl, and C₃₋₆cycloalkyl; R^(11a), R^(14a), R^(14c), R^(15a), R^(17a) and R^(19a) each independently represents hydrogen or C₁₋₄alkyl; R^(14b), R^(14d), R^(15b), R^(17b) and R^(19b) each independently represents hydrogen; C₁₋₄alkyl; C₃₋₆cycloalkyl; or C₁₋₄alkyl substituted with one substituent selected from the group consisting of halo, —OH and —O—C₁₋₄alkyl; R^(20a) and R^(20b) each independently represents hydrogen; C₁₋₄alkyl; C₃₋₆cycloalkyl; or C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —O—C₁₋₄alkyl; p represents 1 or 2; and the pharmaceutically acceptable addition salts, and the solvates thereof.

The present invention relates in particular to compounds of Formula (I) as defined herein, tautomers and stereoisomeric forms thereof, wherein

R¹ represents C₁₋₄alkyl;

R² represents C₁₋₆alkyl, or C₁₋₆alkyl substituted with one R⁵;

Y represents CR⁴ or N;

R⁴ represents hydrogen or halo;

R⁵ represents halo, Het^(3a), —NR^(6a)R^(6b), or —OR⁷;

R^(6a) represents hydrogen or C₁₋₄alkyl;

R^(6b) represents hydrogen; C₁₋₄alkyl; C₃₋₆cycloalkyl; —C(═O)—C₁₋₄alkyl;

—S(═O)₂—C₁₋₄alkyl; —C(═O)—C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —NR^(16a)R^(16b); or C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —S(═O)₂—C₁₋₄alkyl;

R⁷ represents hydrogen, C₁₋₄alkyl, —C₁₋₄alkyl-NR^(8a)R^(8b), —C(═O)—R⁹, —S(═O)₂—OH, —P(═O)₂—OH, —(C═O)—CH(NH₂)—C₁₋₄alkyl-Ar¹, or —C₁₋₄alkyl-Het^(3b);

R^(8a) represents hydrogen or C₁₋₄alkyl;

R^(8b) represents hydrogen, C₁₋₄alkyl, or C₃₋₆cycloalkyl;

R⁹ represents C₁₋₄alkyl, or C₁₋₄alkyl substituted with one substituent selected from the group consisting of —NH₂, —COOH, and Het⁶;

R^(16a) and R^(16b) each independently represents hydrogen, C₁₋₄alkyl or C₃₋₆cycloalkyl;

R³ represents 2-oxo-1,2-dihydropyridin-3-yl,

wherein said 2-oxo-1,2-dihydropyridin-3-yl may optionally substituted on the N-atom with a substituent selected from the group consisting of C₁₋₆alkyl; C₃₋₆cycloalkyl; Het^(1a); R¹⁸; R²¹; C₁₋₄alkyl substituted with one, two or three halo atoms; C₁₋₄alkyl substituted with one, two or three —OH substituents; C₁₋₄alkyl substituted with one R¹³; C₁₋₄alkyl substituted with one R¹⁸; C₂₋₆alkenyl; and C₂₋₆alkenyl substituted with one R¹³; provided that when Het^(1a) or R¹⁸ are directly attached to the N-atom of the 2-oxo-1,2-dihydropyridin-3-yl, said Het^(1a) or R¹⁸ are attached to the N-atom via a ring carbon atom; and wherein said 2-oxo-1,2-dihydropyridin-3-yl may optionally be substituted on the ring carbon atoms with in total one, two or three substituents each independently selected from the group consisting of halo; cyano; C₁₋₆alkyl; —O—C₁₋₄alkyl; —C(═O)—R¹⁰; —S(═O)₂—C₁₋₄alkyl; —S(═O)(═N—R^(20a))—C₁₋₄alkyl; —O—C₁₋₄alkyl substituted with one, two or three halo atoms; —O—C₁₋₄alkyl-R¹²; C₃₋₆cycloalkyl; —O—C₃₋₆cycloalkyl; Het^(1a); —O-Het^(1b); R¹⁸; R²¹; —P(═O)—(C₁₋₄alkyl)₂; —NH—C(═O)—C₁₋₄alkyl; —NH—C(═O)—Het^(1g); —NR^(17a)R^(17b); C₁₋₄alkyl substituted with one, two or three halo atoms; C₁₋₄alkyl substituted with one, two or three —OH substituents; C₁₋₄alkyl substituted with one R¹³; C₁₋₄alkyl substituted with one R¹⁸; C₂₋₆alkenyl; C₂₋₆alkenyl substituted with one R¹³; C₂₋₆alkynyl; and C₂₋₆alkynyl substituted with one R¹³; R¹⁰ represents —OH, —O—C₁₋₄alkyl, —NR^(11a)R^(11b) or Het²; R¹⁸ represents a 5-membered aromatic ring containing one, two or three N-atoms; wherein said 5-membered aromatic ring may optionally be substituted with one substituent selected from the group consisting of C₁₋₄alkyl and C₃₋₆cycloalkyl; R²¹ represents 3,6-dihydro-2H-pyran-4-yl or 1,2,3,6-tetrahydro-4-pyridinyl, wherein 1,2,3,6-tetrahydro-4-pyridinyl may optionally be substituted on the N-atom with C₁₋₄alkyl or C₃₋₆cycloalkyl; Het^(1a), Het^(1c) and Het^(1d) each independently represents a 4- to 7-membered monocyclic saturated heterocyclyl containing one or two heteroatoms each independently selected from O, S, S(═O)_(p) and N; wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted, where possible, on one or two ring N-atoms with a substituent each independently selected from the group consisting of C₁₋₄alkyl, C₃₋₆cycloalkyl, and C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —O—C₁₋₄alkyl; and wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted on one or two ring C-atoms with one or two substituents each independently selected from the group consisting of —OH, halo, C₁₋₄alkyl, cyano, —C(═O)—C₁₋₄alkyl, —O—C₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)₂; Het^(1b), Het^(1e), Het^(1g), Het⁷ and Het⁸ each independently represents a 4- to 7-membered monocyclic saturated heterocyclyl, attached to the remainder of the molecule of Formula (I) through any available ring carbon atom, said Het^(1b), Het^(1e), Het^(1g), Het⁷ and Het⁸ containing one or two heteroatoms each independently selected from O, S, S(═O)_(p) and N; wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted, where possible, on one or two ring N-atoms with a substituent each independently selected from the group consisting of C₁₋₄alkyl, C₃₋₆cycloalkyl, and C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —O—C₁₋₄alkyl; and wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted on one, two or three ring C-atoms with one or two substituents each independently selected from the group consisting of —OH, halo, C₁₋₄alkyl, cyano, —C(═O)—C₁₋₄alkyl, —O—C₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)₂; Het² represents a heterocyclyl of formula (b-1):

(b-1) represents a N-linked 4- to 7-membered monocyclic saturated heterocyclyl optionally containing one additional heteroatom selected from O, S, S(═O)_(p) and N; wherein in case (b-1) contains one additional N-atom, said N-atom may optionally be substituted with a substituent each independently selected from the group consisting of C₁₋₄alkyl, C₃₋₆cycloalkyl and Het⁷; and wherein (b-1) may optionally be substituted on one, two or three ring C-atoms with one or two substituents each independently selected from the group consisting of halo, —OH, cyano, C₁₋₄alkyl, —O—C₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, and C₁₋₄alkyl-OH; R^(11b) represents hydrogen; Het^(1e); C₁₋₄alkyl; —C₁₋₄alkyl-Het⁵; —C₁₋₄alkyl-Het⁸; C₁₋₄alkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, —OH and —O—C₁₋₄alkyl; C₃₋₆cycloalkyl; or C₃₋₆cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, —OH and —O—C₁₋₄alkyl; R¹³ represents —O—C₁₋₄alkyl, —C(═O)NR^(15a)R^(15b), —NR^(19a)R^(19b), C₃₋₆cycloalkyl, Het^(1d), or —C(═O)—Het^(1f); R¹² represents —OH, —O—C₁₋₄alkyl, —NR^(14a)R^(14b), —C(═O)NR^(14c)R^(14d), —S(═O)₂—C₁₋₄alkyl, —S(═O)(═N—R^(2b))—C₁₋₄alkyl, C₃₋₆cycloalkyl, Ar², or Het^(1c); Ar¹ represents phenyl optionally substituted with one hydroxy; Ar² represents phenyl optionally substituted with one C₁₋₄alkyl; Het^(3a), Het^(3b), Het⁵, Het⁶ and Het^(1f) each independently represents a heterocyclyl of formula (c-1):

(c-1) represents a N-linked 4- to 7-membered monocyclic saturated heterocyclyl optionally containing one additional heteroatom selected from O, S, S(═O)_(p) and N; wherein in case (c-1) contains one additional N-atom, said additional N-atom may optionally be substituted with C₁₋₄alkyl or C₃₋₆cycloalkyl; and wherein (c-1) may optionally be substituted on one or two ring C-atoms atoms with one or two substituents each independently selected from the group consisting of halo, C₁₋₄alkyl, and C₃₋₆cycloalkyl; R^(11a), R^(14a), R^(14c), R^(15a), R^(17a) and R^(19a) each independently represents hydrogen or C₁₋₄alkyl; R^(14b), R^(14d), R^(15b), R^(17b) and R^(19b) each independently represents hydrogen; C₁₋₄alkyl; C₃₋₆cycloalkyl; —C(═O)—C₁₋₄alkyl; C₁₋₄alkyl substituted with one substituent selected from the group consisting of halo, —OH and —O—C₁₋₄alkyl; —C(═O)—C₁₋₄alkyl substituted with one substituent selected from the group consisting of halo, —OH and —O—C₁₋₄alkyl; or —S(═O)₂—C₁₋₄alkyl; R^(20a) and R^(20b) each independently represents hydrogen; C₁₋₄alkyl; C₃₋₆cycloalkyl; or C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —O—C₁₋₄alkyl; p represents 1 or 2; and the pharmaceutically acceptable addition salts, and the solvates thereof.

The present invention relates in particular to compounds of Formula (I) as defined herein, tautomers and stereoisomeric forms thereof, wherein

R¹ represents C₁₋₄alkyl;

R² represents C₁₋₆alkyl, or C₁₋₆alkyl substituted with one R⁵;

Y represents CR⁴;

R⁴ represents hydrogen or halo;

R⁵ represents Het^(3a), —NR^(6a)R^(6b), or —OR⁷;

R^(6a) represents hydrogen or C₁₋₄alkyl;

R^(6b) represents hydrogen; C₁₋₄alkyl; C₃₋₆cycloalkyl; —C(═O)—C₁₋₄alkyl;

—S(═O)₂—C₁₋₄alkyl; —C(═O)—C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —NR^(16a)R^(16b); or C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —S(═O)₂—C₁₋₄alkyl;

R⁷ represents hydrogen, C₁₋₄alkyl, —C₁₋₄alkyl-NR^(8a)R^(8b), —C(═O)—R⁹, —S(═O)₂—OH, —P(═O)₂—OH, —(C═O)—CH(NH₂)—C₁₋₄alkyl-Ar¹, or —C₁₋₄alkyl-Het^(3b);

R^(8a) represents hydrogen or C₁₋₄alkyl;

R^(8b) represents hydrogen, C₁₋₄alkyl, or C₃₋₆cycloalkyl;

R⁹ represents C₁₋₄alkyl, or C₁₋₄alkyl substituted with one substituent selected from the group consisting of —NH₂, —COOH, and Het⁶;

R^(16a) and R^(16b) each independently represents hydrogen, C₁₋₄alkyl or C₃₋₆cycloalkyl;

R³ represents 2-oxo-1,2-dihydropyridin-3-yl,

wherein said 2-oxo-1,2-dihydropyridin-3-yl may optionally substituted on the N-atom with a substituent selected from the group consisting of C₁₋₆alkyl; C₃₋₆cycloalkyl; Het^(1a); R¹⁸; R²¹; C₁₋₄alkyl substituted with one, two or three halo atoms; C₁₋₄alkyl substituted with one, two or three —OH substituents; C₁₋₄alkyl substituted with one R¹³; C₁₋₄alkyl substituted with one R¹⁸; C₂₋₆alkenyl; and C₂₋₆alkenyl substituted with one R¹³; provided that when Het^(1a) or R¹⁸ are directly attached to the N-atom of the 2-oxo-1,2-dihydropyridin-3-yl, said Het^(1a) or R¹⁸ are attached to the N-atom via a ring carbon atom; and wherein said 2-oxo-1,2-dihydropyridin-3-yl may optionally be substituted on the ring carbon atoms with in total one, two or three substituents each independently selected from the group consisting of halo; cyano; C₁₋₆alkyl; —O—C₁₋₄alkyl; —C(═O)—R¹⁰; —S(═O)₂—C₁₋₄alkyl; —S(═O)(═N—R^(20a))—C₁₋₄alkyl; —O—C₁₋₄alkyl substituted with one, two or three halo atoms; —O—C₁₋₄alkyl-R¹²; C₃₋₆cycloalkyl; —O—C₃₋₆cycloalkyl; Het^(1a); —O-Het^(1b); R¹⁸; R²¹; —P(═O)—(C₁₋₄alkyl)₂; —NH—C(═O)—C₁₋₄alkyl; —NH—C(═O)—Het^(1g); —NR^(7a)R^(17b); C₁₋₄alkyl substituted with one, two or three halo atoms; C₁₋₄alkyl substituted with one, two or three —OH substituents; C₁₋₄alkyl substituted with one R¹³; C₁₋₄alkyl substituted with one R¹⁸; C₂₋₆alkenyl; and C₂₋₆alkenyl substituted with one R¹³; R¹⁰ represents —OH, —O—C₁₋₄alkyl, —NR^(11a)R^(11b) or Het²; R¹⁸ represents a 5-membered aromatic ring containing one, two or three N-atoms; wherein said 5-membered aromatic ring may optionally be substituted with one substituent selected from the group consisting of C₁₋₄alkyl and C₃₋₆cycloalkyl; R²¹ represents 3,6-dihydro-2H-pyran-4-yl or 1,2,3,6-tetrahydro-4-pyridinyl, wherein 1,2,3,6-tetrahydro-4-pyridinyl may optionally be substituted on the N-atom with C₁₋₄alkyl or C₃₋₆cycloalkyl; Het^(1a), Het^(1c) and Het^(1d) each independently represents a 4- to 7-membered monocyclic saturated heterocyclyl containing one or two heteroatoms each independently selected from O, S, S(═O)_(p) and N; wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted, where possible, on one or two ring N-atoms with a substituent each independently selected from the group consisting of C₁₋₄alkyl, C₃₋₆cycloalkyl, and C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —O—C₁₋₄alkyl; and wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted on one or two ring C-atoms with one or two substituents each independently selected from the group consisting of —OH, halo, C₁₋₄alkyl, cyano, —C(═O)—C₁₋₄alkyl, —O—C₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)₂; Het^(1b), Het^(1e) and Het^(1g) each independently represents a 4- to 7-membered monocyclic saturated heterocyclyl, attached to the remainder of the molecule of Formula (I) through any available ring carbon atom, said Het^(1b), Het^(1e) and Het^(1g) containing one or two heteroatoms each independently selected from O, S, S(═O)_(p) and N; wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted, where possible, on one or two ring N-atoms with a substituent each independently selected from the group consisting of C₁₋₄alkyl, C₃₋₆cycloalkyl, and C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —O—C₁₋₄alkyl; and wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted on one, two or three ring C-atoms with one or two substituents each independently selected from the group consisting of —OH, halo, C₁₋₄alkyl, cyano, —C(═O)—C₁₋₄alkyl, —O—C₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)₂; Het² represents a heterocycyl of formula (b-1):

(b-1) represents a N-linked 4- to 7-membered monocyclic saturated heterocyclyl optionally containing one additional heteroatom selected from O, S, S(═O)_(p) and N; wherein in case (b-1) contains one additional N-atom, said N-atom may optionally be substituted with C₁₋₄alkyl; and wherein (b-1) may optionally be substituted on one, two or three ring C-atoms with one or two substituents each independently selected from the group consisting of halo, —OH, cyano, C₁₋₄alkyl, —O—C₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, and C₁₋₄alkyl-OH; R^(11b) represents hydrogen; Het^(1e); C₁₋₄alkyl; —C₁₋₄alkyl-Het⁵; C₁₋₄alkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, —OH and —O—C₁₋₄alkyl; C₃₋₆cycloalkyl; or C₃₋₆cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, —OH and —O—C₁₋₄alkyl; R¹³ represents —O—C₁₋₄alkyl, —C(═O)NR^(15a)R^(15b), —NR^(19a)R^(19b), C₃₋₆cycloalkyl, Het^(1d), or —C(═O)—Het^(1f); R¹² represents —OH, —O—C₁₋₄alkyl, —NR^(14a)R^(14b), —C(═O)NR^(14c)R^(14d), —S(═O)₂—C₁₋₄alkyl, —S(═O)(═N—R^(20b))—C₁₋₄alkyl, C₃₋₆cycloalkyl, Ar², or Het^(1c); Ar¹ represents phenyl optionally substituted with one hydroxy; Ar² represents phenyl optionally substituted with one C₁₋₄alkyl; Het^(3a), Het^(3b), Het⁵, Het⁶ and Het^(1f) each independently represents a heterocyclyl of formula (c-1):

(c-1) represents a N-linked 4- to 7-membered monocyclic saturated heterocyclyl optionally containing one additional heteroatom selected from O, S, S(═O)_(p) and N; wherein in case (c-1) contains one additional N-atom, said additional N-atom may optionally be substituted with C₁₋₄alkyl or C₃₋₆cycloalkyl; and wherein (c-1) may optionally be substituted on one or two ring C-atoms atoms with one or two substituents each independently selected from the group consisting of halo, C₁₋₄alkyl, and C₃₋₆cycloalkyl; R^(11a), R^(14a), R^(14c), R^(15a), R^(17a) and R^(19a) each independently represents hydrogen or C₁₋₄alkyl; R^(14b), R^(14d), R^(15b), R^(17b) and R^(19b) each independently represents hydrogen; C₁₋₄alkyl; C₃₋₆cycloalkyl; or C₁₋₄alkyl substituted with one substituent selected from the group consisting of halo, —OH and —O—C₁₋₄alkyl; R^(20a) and R^(20b) each independently represents hydrogen; C₁₋₄alkyl; C₃₋₆cycloalkyl; or C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —O—C₁₋₄alkyl; p represents 1 or 2; and the pharmaceutically acceptable addition salts, and the solvates thereof.

The present invention relates in particular to compounds of Formula (I) as defined herein, tautomers and stereoisomeric forms thereof, wherein

R¹ represents C₁₋₄alkyl;

R² represents C₁₋₆alkyl, or C₁₋₆alkyl substituted with one R⁵;

Y represents CR⁴ or N;

R⁴ represents hydrogen or halo;

R⁵ represents Het³a, —NR^(6a)R^(6b), or —OR⁷;

R^(6a) represents hydrogen or C₁₋₄alkyl;

R^(6b) represents C₁₋₄alkyl; C₃₋₆cycloalkyl; —C(═O)—C₁₋₄alkyl; or C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —S(═O)₂—C₁₋₄alkyl;

R⁷ represents hydrogen, C₁₋₄alkyl, —C₁₋₄alkyl-NR^(8a)R^(8b), —C(═O)—R⁹, or —C₁₋₄alkyl-Het^(3b);

R^(8a) represents hydrogen;

R^(8b) represents C₁₋₄alkyl, or C₃₋₆cycloalkyl;

R⁹ represents C₁₋₄alkyl, or C₁₋₄alkyl substituted with one substituent selected from the group consisting of —NH₂;

R³ represents a 6-membered heteroaromatic ring containing 1 or 2 N-atoms, optionally substituted with one, two or three substituents each independently selected from the group consisting of halo; cyano; C₁₋₆alkyl; —O—C₁₋₄alkyl; —C(═O)—R¹⁰; —O—C₁₋₄alkyl-R¹²; C₃₋₆cycloalkyl; —O—C₃₋₆cycloalkyl; Het^(1a); —O-Het^(1b); C₁₋₄alkyl substituted with one, two or three —OH substituents; R¹⁸; R²¹; —P(═O)—(C₁₋₄alkyl)₂; —NR^(17a)R^(17b); C₁₋₄alkyl substituted with one, two or three halo atoms; C₁₋₄alkyl substituted with one R¹³; C₂₋₆alkenyl; and C₂₋₆alkenyl substituted with one R¹³; or R³ represents 2-oxo-1,2-dihydropyridin-3-yl, wherein said 2-oxo-1,2-dihydropyridin-3-yl may optionally substituted on the N-atom with a substituent selected from the group consisting of C₁₋₆alkyl; C₁₋₄alkyl substituted with one, two or three —OH substituents; C₁₋₄alkyl substituted with one R¹³; C₁₋₄alkyl substituted with one R¹⁸; and wherein said 2-oxo-1,2-dihydropyridin-3-yl may optionally be substituted on the ring carbon atoms with in total one, two or three substituents each independently selected from the group consisting of halo; C₁₋₆alkyl; —C(═O)—Ro; and Het^(1a); R¹⁰ represents —O—C₁₋₄alkyl, —NR^(11a)R^(11b) or Het²; R¹⁸ represents a 5-membered aromatic ring containing one, two or three N-atoms; wherein said 5-membered aromatic ring may optionally be substituted with one substituent selected from the group consisting of C₁₋₄alkyl and C₃₋₆cycloalkyl; R²¹ represents 3,6-dihydro-2H-pyran-4-yl; Het^(1a), Het^(1c) and Het^(1d) each independently represents a 4- to 7-membered monocyclic saturated heterocyclyl containing one or two heteroatoms each independently selected from O and N; wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted, where possible, on one or two ring N-atoms with a substituent each independently selected from the group consisting of C₁₋₄alkyl, C₃₋₆cycloalkyl, and C₁₋₄alkyl substituted with one —OH substituent; and wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted on one, two or three ring C-atoms with one or two substituents each independently selected from the group consisting of halo and C₁₋₄alkyl; Het^(1b) represents a 4- to 7-membered monocyclic saturated heterocyclyl, attached to the remainder of the molecule of Formula (I) through any available ring carbon atom, said Het^(1b) containing one or two heteroatoms each independently selected from O and N; wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted, where possible, on one or two ring N-atoms with a substituent each independently selected from the group consisting of C₁₋₄alkyl and C₃₋₆cycloalkyl; wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted on one, two or three ring C-atoms with one or two halo substituents; Het² represents a heterocyclyl of formula (b-1):

(b-1) represents a N-linked 4- to 7-membered monocyclic saturated heterocyclyl optionally containing one additional N-atom; wherein in case (b-1) contains one additional N-atom, said one N-atom may optionally be substituted with C₁₋₄alkyl; wherein (b-1) may optionally be substituted on one, two or three ring C-atoms with one or two —OH substituents; R^(11b) represents C₁₋₄alkyl; R¹³ represents —O—C₁₋₄alkyl, —C(═O)NR^(15a)R^(15b), —NR^(19a)R^(19b), C₃₋₆cycloalkyl, or Het^(1d); R¹² represents —OH, —O—C₁₋₄alkyl, —C(═O)NR^(14c)R^(14d), C₃₋₆cycloalkyl, or Het^(1c); Het^(3a) and Het^(3b) each independently represents a heterocyclyl of formula (c-1):

(c-1) represents a N-linked 4- to 7-membered monocyclic saturated heterocyclyl optionally containing one additional heteroatom selected from O and N; R^(11a), R^(14c), R^(15a), R^(17a) and R^(19a) each independently represents hydrogen or C₁₋₄alkyl; R^(14d), R^(15b), R^(17b) and R^(19b) each independently represents C₁₋₄alkyl; C₃₋₆cycloalkyl; or C₁₋₄alkyl substituted with one —O—C₁₋₄alkyl substituent; and the pharmaceutically acceptable addition salts, and the solvates thereof.

The present invention relates in particular to compounds of Formula (I) as defined herein, tautomers and stereoisomeric forms thereof, wherein

R¹ represents C₁₋₄alkyl;

R² represents C₁₋₆alkyl, or C₁₋₆alkyl substituted with one R⁵;

Y represents CR⁴ or N;

R⁴ represents hydrogen or halo;

R⁵ represents halo, —NR^(6a)R^(6b), or —OR⁷;

R^(6a) represents hydrogen or C₁₋₄alkyl;

R^(6b) represents hydrogen; C₁₋₄alkyl; C₃₋₆cycloalkyl; —C(═O)—C₁₋₄alkyl;

—S(═O)₂—C₁₋₄alkyl; —C(═O)—C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —NR^(16a)R^(16b); or C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —S(═O)₂—C₁₋₄alkyl;

R⁷ represents hydrogen, C₁₋₄alkyl, —C₁₋₄alkyl-NR^(8a)R^(8b), —C(═O)—R⁹, —S(═O)₂—OH,

—P(═O)₂—OH, or —(C═O)—CH(NH₂)—C₁₋₄alkyl-Ar¹;

R^(8a) represents hydrogen or C₁₋₄alkyl;

R^(8b) represents hydrogen, C₁₋₄alkyl, or C₃₋₆cycloalkyl;

R⁹ represents C₁₋₄alkyl, or C₁₋₄alkyl substituted with one substituent selected from the group consisting of —NH₂ and —COOH;

R^(16a) and R^(16b) each independently represents hydrogen, C₁₋₄alkyl or C₃₋₆cycloalkyl;

R³ represents a 6-membered heteroaromatic ring containing 1 or 2 N-atoms, optionally substituted with one, two or three substituents each independently selected from the group consisting of halo; cyano; C₁₋₆alkyl; —O—C₁₋₄alkyl; —C(═O)—R¹⁰; —S(═O)₂—C₁₋₄alkyl; —S(═O)(═N—R^(20a))—C₁₋₄alkyl; —O—C₁₋₄alkyl substituted with one, two or three halo atoms; —O—C₁₋₄alkyl-R¹²; C₃₋₆cycloalkyl; —O—C₃₋₆cycloalkyl; —P(═O)—(C₁₋₄alkyl)₂; —NH—C(═O)—C₁₋₄alkyl; —NR^(17a)R^(17b); C₁₋₄alkyl substituted with one, two or three halo atoms; C₁₋₄alkyl substituted with one, two or three —OH substituents; C₁₋₄alkyl substituted with one R¹³; C₂₋₆alkenyl; C₂₋₆alkenyl substituted with one R¹³; C₂₋₆alkynyl; and C₂₋₆alkynyl substituted with one R¹³; R¹⁰ represents —OH, —O—C₁₋₄alkyl or —NR^(11a)R^(11b); R^(11b) represents hydrogen; C₁₋₄alkyl; C₁₋₄alkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, —OH and —O—C₁₋₄alkyl; C₃₋₆cycloalkyl; or C₃₋₆cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, —OH and —O—C₁₋₄alkyl; R¹³ represents —O—C₁₋₄alkyl, —C(═O)NR^(15a)R^(15b), —NR^(19a)R^(19b), C₃₋₆cycloalkyl; R¹² represents —OH, —O—C₁₋₄alkyl, —NR^(14a)R^(14b), —C(═O)NR^(14c)R^(14d), —S(═O)₂—C₁₋₄alkyl, —S(═O)(═N—R^(20b))—C₁₋₄alkyl, C₃₋₆cycloalkyl, Ar²; Ar¹ represents phenyl optionally substituted with one hydroxy; Ar² represents phenyl optionally substituted with one C₁₋₄alkyl; R^(11a), R^(14a), R^(14c), R^(15a), R^(17a) and R^(19a) each independently represents hydrogen or C₁₋₄alkyl; R^(14b), R^(14d), R^(15b), R^(17b) and R^(19b) each independently represents hydrogen; C₁₋₄alkyl; C₃₋₆cycloalkyl; —C(═O)—C₁₋₄alkyl; C₁₋₄alkyl substituted with one substituent selected from the group consisting of halo, —OH and —O—C₁₋₄alkyl; —C(═O)—C₁₋₄alkyl substituted with one substituent selected from the group consisting of halo, —OH and —O—C₁₋₄alkyl; or —S(═O)₂—C₁₋₄alkyl; R^(20a) and R^(20b) each independently represents hydrogen; C₁₋₄alkyl; C₃₋₆cycloalkyl; or C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —O—C₁₋₄alkyl; p represents 1 or 2; and the pharmaceutically acceptable addition salts, and the solvates thereof.

The present invention relates in particular to compounds of Formula (I) as defined herein, tautomers and stereoisomeric forms thereof, wherein

R¹ represents C₁₋₄alkyl;

R² represents C₁₋₆alkyl, or C₁₋₆alkyl substituted with one R⁵;

Y represents CR⁴;

R⁴ represents hydrogen or halo;

R⁵ represents —NR^(6a)R^(6b), or —OR⁷;

R^(6a) represents hydrogen or C₁₋₄alkyl;

R^(6b) represents hydrogen; C₁₋₄alkyl; C₃₋₆cycloalkyl; —C(═O)—C₁₋₄alkyl;

—S(═O)₂—C₁₋₄alkyl; —C(═O)—C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —NR^(16a)R^(16b); or C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —S(═O)₂—C₁₋₄alkyl;

R⁷ represents hydrogen, C₁₋₄alkyl, —C₁₋₄alkyl-NR^(8a)R^(8b), —C(═O)—R⁹, —S(═O)₂—OH, —P(═O)₂—OH, or —(C═O)—CH(NH₂)—C₁₋₄alkyl-Ar¹;

R^(8a) represents hydrogen or C₁₋₄alkyl;

R^(8b) represents hydrogen, C₁₋₄alkyl, or C₃₋₆cycloalkyl;

R⁹ represents C₁₋₄alkyl, or C₁₋₄alkyl substituted with one substituent selected from the group consisting of —NH₂ and —COOH;

R^(16a) and R^(16b) each independently represents hydrogen, C₁₋₄alkyl or C₃₋₆cycloalkyl;

R³ represents a 6-membered heteroaromatic ring containing 1 or 2 N-atoms, optionally substituted with one, two or three substituents each independently selected from the group consisting of halo; cyano; C₁₋₆alkyl; —O—C₁₋₄alkyl; —C(═O)—R¹⁰; —S(═O)₂—C₁₋₄alkyl; —S(═O)(═N—R^(20a))—C₁₋₄alkyl; —O—C₁₋₄alkyl substituted with one, two or three halo atoms; —O—C₁₋₄alkyl-R¹²; C₃₋₆cycloalkyl; —O—C₃₋₆cycloalkyl; —P(═O)—(C₁₋₄alkyl)₂; —NH—C(═O)—C₁₋₄alkyl; —NR^(17a)R^(17b); C₁₋₄alkyl substituted with one, two or three halo atoms; C₁₋₄alkyl substituted with one, two or three —OH substituents; C₁₋₄alkyl substituted with one R¹³; C₂₋₆alkenyl; and C₂₋₆alkenyl substituted with one R¹³; R¹⁰ represents —OH, —O—C₁₋₄alkyl or —NR^(11a)R^(11b); R^(11b) represents hydrogen; C₁₋₄alkyl; C₁₋₄alkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, —OH and —O—C₁₋₄alkyl; C₃₋₆cycloalkyl; or C₃₋₆cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, —OH and —O—C₁₋₄alkyl; R¹³ represents —O—C₁₋₄alkyl, —C(═O)NR^(15a)R^(15b), —NR^(19a)R^(19b), C₃₋₆cycloalkyl; R¹² represents —OH, —O—C₁₋₄alkyl, —NR^(14a)R^(14b), —C(═O)NR^(14c)R^(14d), —S(═O)₂—C₁₋₄alkyl, —S(═O)(═N—R^(20b))—C₁₋₄alkyl, C₃₋₆cycloalkyl, Ar²; Ar¹ represents phenyl optionally substituted with one hydroxy; Ar² represents phenyl optionally substituted with one C₁₋₄alkyl; R^(11a), R^(14a), R^(14c), R^(15a), R^(17a) and R^(19a) each independently represents hydrogen or C₁₋₄alkyl; R^(14b), R^(14d), R^(15b), R^(17b) and R^(19b) each independently represents hydrogen; C₁₋₄alkyl; C₃₋₆cycloalkyl; or C₁₋₄alkyl substituted with one substituent selected from the group consisting of halo, —OH and —O—C₁₋₄alkyl; R^(20a) and R^(20b) each independently represents hydrogen; C₁₋₄alkyl; C₃₋₆cycloalkyl; or C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —O—C₁₋₄alkyl; p represents 1 or 2; and the pharmaceutically acceptable addition salts, and the solvates thereof.

The present invention relates in particular to compounds of Formula (I) as defined herein, tautomers and stereoisomeric forms thereof, wherein

R¹ represents C₁₋₄alkyl;

R² represents C₁₋₆alkyl, or C₁₋₆alkyl substituted with one R⁵;

Y represents CR⁴;

R⁴ represents hydrogen or halo;

R⁵ represents Het^(3a), —NR^(6a)R^(6b), or —OR⁷;

R^(6a) represents hydrogen or C₁₋₄alkyl;

R^(6b) represents C₁₋₄alkyl; C₃₋₆cycloalkyl; —C(═O)—C₁₋₄alkyl; or C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —S(═O)₂—C₁₋₄alkyl;

R⁷ represents hydrogen, C₁₋₄alkyl, —C₁₋₄alkyl-NR^(8a)R^(8b), —C(═O)—R⁹, or —C₁₋₄alkyl-Het^(3b);

R^(8a) represents hydrogen;

R^(8b) represents C₁₋₄alkyl, or C₃₋₆cycloalkyl;

R⁹ represents C₁₋₄alkyl, or C₁₋₄alkyl substituted with one substituent selected from the group consisting of —NH₂;

R³ represents a 6-membered heteroaromatic ring containing 1 or 2 N-atoms, optionally substituted with one, two or three substituents each independently selected from the group consisting of halo; cyano; C₁₋₆alkyl; —O—C₁₋₄alkyl; —C(═O)—R¹⁰; —O—C₁₋₄alkyl-R¹²; C₃₋₆cycloalkyl; —O—C₃₋₆cycloalkyl; Het^(1a); —O-Het^(1b); R¹⁸; R²¹; —P(═O)—(C₁₋₄alkyl)₂; —NR^(17a)R^(17b); C₁₋₄alkyl substituted with one, two or three halo atoms; C₁₋₄alkyl substituted with one R¹³; C₂₋₆alkenyl; and C₂₋₆alkenyl substituted with one R¹³; R¹⁰ represents —O—C₁₋₄alkyl, —NR^(11a)R^(11b) or Het²; R¹⁸ represents a 5-membered aromatic ring containing one, two or three N-atoms; wherein said 5-membered aromatic ring may optionally be substituted with one C₁₋₄alkyl substituent; R²¹ represents 3,6-dihydro-2H-pyran-4-yl; Het^(1a) and Het^(1c) each independently represents a 4- to 7-membered monocyclic saturated heterocyclyl containing one or two heteroatoms each independently selected from O and N; wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted, where possible, on one or two ring N-atoms with a substituent each independently selected from the group consisting of C₁₋₄alkyl, and C₁₋₄alkyl substituted with one —OH substituent; and wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted on one, two or three ring C-atoms with one or two C₁₋₄alkyl substituents; Het^(1b) represents a 4- to 7-membered monocyclic saturated heterocyclyl, attached to the remainder of the molecule of Formula (I) through any available ring carbon atom, said Het^(1b) containing one or two heteroatoms each independently selected from O and N; wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted, where possible, on one or two ring N-atoms with a C₁₋₄alkyl substituent; Het² represents a heterocyclyl of formula (b-1):

(b-1) represents a N-linked 4- to 7-membered monocyclic saturated heterocyclyl optionally containing one additional N-atom; wherein in case (b-1) contains one additional N-atom, said one N-atom may optionally be substituted with C₁₋₄alkyl; R^(11b) represents C₁₋₄alkyl; R¹³ represents —O—C₁₋₄alkyl, —C(═O)NR^(15a)R^(15b), or C₃₋₆cycloalkyl; R¹² represents —OH, —O—C₁₋₄alkyl, —C(═O)NR^(14c)R^(14d), C₃₋₆cycloalkyl, or Het^(1c); Het^(3a) and Het^(3b) each independently represents a heterocyclyl of formula (c-1):

(c-1) represents a N-linked 4- to 7-membered monocyclic saturated heterocyclyl optionally containing one additional heteroatom selected from O and N; R^(11a), R^(14c), R^(15a), R^(17a) each independently represents hydrogen or C₁₋₄alkyl; R^(14d), R^(15b), R^(17b) each independently represents C₁₋₄alkyl; or C₁₋₄alkyl substituted with one —O—C₁₋₄alkyl substituent; and the pharmaceutically acceptable addition salts, and the solvates thereof.

The present invention relates in particular to compounds of Formula (I) as defined herein, tautomers and stereoisomeric forms thereof, wherein

R¹ represents C₁₋₄alkyl;

R² represents C₁₋₆alkyl, or C₁₋₆alkyl substituted with one R⁵;

Y represents CR⁴;

R⁴ represents hydrogen or halo;

R⁵ represents Het^(3a), —NR^(6a)R^(6b), or —OR⁷;

R^(6a) represents hydrogen or C₁₋₄alkyl;

R^(6b) represents C₁₋₄alkyl; C₃₋₆cycloalkyl; —C(═O)—C₁₋₄alkyl; or C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —S(═O)₂—C₁₋₄alkyl;

R⁷ represents hydrogen, C₁₋₄alkyl, —C₁₋₄alkyl-NR^(8a)R^(8b), —C(═O)—R⁹, or —C₁₋₄alkyl-Het^(3b);

R^(8a) represents hydrogen;

R^(8b) represents C₁₋₄alkyl, or C₃₋₆cycloalkyl;

R⁹ represents C₁₋₄alkyl, or C₁₋₄alkyl substituted with one substituent selected from the group consisting of —NH₂;

R³ represents a 6-membered heteroaromatic ring containing 1 or 2 N-atoms, optionally substituted with one, two or three substituents each independently selected from the group consisting of halo; cyano; C₁₋₆alkyl; —O—C₁₋₄alkyl; —C(═O)—R¹⁰; —O—C₁₋₄alkyl-R¹²; C₃₋₆cycloalkyl; —O—C₃₋₆cycloalkyl; Het^(1a); —O-Het^(1b); R¹⁸; R²¹; —P(═O)—(C₁₋₄alkyl)₂; —NR^(17a)R^(17b); C₁₋₄alkyl substituted with one, two or three halo atoms; C₁₋₄alkyl substituted with one R¹³; C₂₋₆alkenyl; and C₂₋₆alkenyl substituted with one R¹³; R¹⁰ represents —O—C₁₋₄alkyl, or —NR^(11a)R^(11b); R¹⁸ represents a 5-membered aromatic ring containing one, two or three N-atoms; wherein said 5-membered aromatic ring may optionally be substituted with one C₁₋₄alkyl substituent; R²¹ represents 3,6-dihydro-2H-pyran-4-yl; Het^(1a) a and Het^(1c) each independently represents a 4- to 7-membered monocyclic saturated heterocyclyl containing one or two heteroatoms each independently selected from O and N; wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted, where possible, on one, two or three ring N-atoms with a substituent each independently selected from the group consisting of C₁₋₄alkyl, and C₁₋₄alkyl substituted with one —OH substituent; and wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted on one, two or three ring C-atoms with one or two C₁₋₄alkyl substituents; Het^(1b) represents a 4- to 7-membered monocyclic saturated heterocyclyl, attached to the remainder of the molecule of Formula (I) through any available ring carbon atom, said Het^(1b) containing one or two heteroatoms each independently selected from O and N; wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted, where possible, on one or two ring N-atoms with a C₁₋₄alkyl substituent; R^(11b) represents C₁₋₄alkyl; R¹³ represents —O—C₁₋₄alkyl, —C(═O)NR^(15a)R^(15b), or C₃₋₆cycloalkyl; R¹² represents —OH, —O—C₁₋₄alkyl, —C(═O)NR^(14c)R^(14d), C₃₋₆cycloalkyl, or Het^(1c); Het^(3a) and Het^(3b) each independently represents a heterocyclyl of formula (c-1):

(c-1) represents a N-linked 4- to 7-membered monocyclic saturated heterocyclyl optionally containing one additional heteroatom selected from O and N; R^(11a), R^(14c), R^(15a), R^(17a) each independently represents hydrogen or C₁₋₄alkyl; R^(14d), R^(15b), R^(17b) each independently represents C₁₋₄alkyl; or C₁₋₄alkyl substituted with one —O—C₁₋₄alkyl substituent; and the pharmaceutically acceptable addition salts, and the solvates thereof.

The present invention relates in particular to compounds of Formula (I) as defined herein, tautomers and stereoisomeric forms thereof, wherein

R¹ represents C₁₋₄alkyl;

R² represents C₁₋₆alkyl substituted with one R⁵;

Y represents CR⁴;

R⁴ represents hydrogen or halo;

R⁵ represents —NR^(6a)R^(6b), or —OR⁷;

R^(6a) represents hydrogen;

R^(6b) represents —C(═O)—C₁₋₄alkyl;

R⁷ represents hydrogen;

R³ represents a 6-membered heteroaromatic ring containing 1 or 2 N-atoms, optionally substituted with one, two or three substituents each independently selected from the group consisting of halo; cyano; C₁₋₆alkyl; —O—C₁₋₄alkyl; —C(═O)—R¹⁰; —O—C₁₋₄alkyl-R¹²; Het^(1a); —NR^(17a)R^(17b); C₁₋₄alkyl substituted with one R¹³; R¹⁰ represents —NR^(11a)R^(11b); Het^(1a) represents a 4- to 7-membered monocyclic saturated heterocyclyl containing one or two heteroatoms each independently selected from O and N; wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted, where possible, on one or two ring N-atoms with a substituent each independently selected from the group consisting of C₁₋₄alkyl, and C₁₋₄alkyl substituted with one —OH substituent; R^(11a) represents hydrogen or C₁₋₄alkyl; R^(11b) represents C₁₋₄alkyl; R¹³ represents —O—C₁₋₄alkyl; R¹² represents —O—C₁₋₄alkyl; R^(17a) represents hydrogen; R^(17b) represents C₁₋₄alkyl substituted with one —O—C₁₋₄alkyl substituent; and the pharmaceutically acceptable addition salts, and the solvates thereof.

The present invention relates in particular to compounds of Formula (I) as defined herein, tautomers and stereoisomeric forms thereof, wherein

R¹ represents C₁₋₄alkyl;

R² represents C₁₋₆alkyl substituted with one R⁵;

Y represents CR⁴;

R⁴ represents hydrogen or halo;

R⁵ represents —NR^(6a)R^(6b), or —OR⁷;

R^(6a) represents hydrogen;

R^(6b) represents —C(═O)—C₁₋₄alkyl;

R⁷ represents hydrogen;

R³ represents a 6-membered heteroaromatic ring containing 1 or 2 N-atoms, optionally substituted with one, two or three substituents each independently selected from the group consisting of halo; cyano; C₁₋₆alkyl; —O—C₁₋₄alkyl; —C(═O)—R¹⁰; —O—C₁₋₄alkyl-R¹²; —NR^(17a)R^(17b); C₁₋₄alkyl substituted with one R¹³; R¹⁰ represents —NR^(11a)R^(11b); R^(11a) represents hydrogen or C₁₋₄alkyl; R^(11b) represents C₁₋₄alkyl; R¹³ represents —O—C₁₋₄alkyl; R¹² represents —O—C₁₋₄alkyl; R^(17a) represents hydrogen; R^(17b) represents C₁₋₄alkyl substituted with one —O—C₁₋₄alkyl substituent; and the pharmaceutically acceptable addition salts, and the solvates thereof.

The present invention relates in particular to compounds of Formula (I) as defined herein, tautomers and stereoisomeric forms thereof, wherein

R¹ represents C₁₋₄alkyl;

R² represents C₁₋₆alkyl substituted with one R⁵;

Y represents CR⁴;

R⁴ represents hydrogen;

R⁵ represents-OR⁷;

R⁷ represents hydrogen;

R³ represents a 6-membered heteroaromatic ring containing 1 or 2 N-atoms, optionally substituted with one, two or three substituents each independently selected from the group consisting of halo; cyano; C₁₋₆alkyl; —O—C₁₋₄alkyl; —C(═O)—R¹⁰; —O—C₁₋₄alkyl-R¹²; Het^(1a); —NR^(17a)R^(17b); C₁₋₄alkyl substituted with one R¹³; R¹⁰ represents —NR^(11a)R^(11b); Het^(1a) represents a 4- to 7-membered monocyclic saturated heterocyclyl containing one or two heteroatoms each independently selected from O and N; wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted, where possible, on one or two ring N-atoms with a substituent each independently selected from the group consisting of C₁₋₄alkyl, and C₁₋₄alkyl substituted with one —OH substituent; R^(11a) represents hydrogen or C₁₋₄alkyl; R^(11b) represents C₁₋₄alkyl; R¹³ represents —O—C₁₋₄alkyl; R¹² represents —O—C₁₋₄alkyl; R^(17a) represents hydrogen; R^(17b) represents C₁₋₄alkyl substituted with one —O—C₁₋₄alkyl substituent; and the pharmaceutically acceptable addition salts, and the solvates thereof.

The present invention relates in particular to compounds of Formula (I) as defined herein, tautomers and stereoisomeric forms thereof, wherein

R¹ represents C₁₋₄alkyl;

R² represents C₁₋₆alkyl substituted with one R⁵;

Y represents CR⁴;

R⁴ represents hydrogen;

R⁵ represents-OR⁷;

R⁷ represents hydrogen;

R³ represents a 6-membered heteroaromatic ring containing 1 or 2 N-atoms, optionally substituted with one, two or three substituents each independently selected from the group consisting of halo; cyano; C₁₋₆alkyl; —O—C₁₋₄alkyl; —C(═O)—R¹⁰; —O—C₁₋₄alkyl-R¹²; —NR^(17a)R^(17b); C₁₋₄alkyl substituted with one R¹³; R¹⁰ represents —NR^(11a)R^(11b); R^(11a) represents hydrogen or C₁₋₄alkyl; R^(11b) represents C₁₋₄alkyl; R¹³ represents —O—C₁₋₄alkyl; R¹² represents —O—C₁₋₄alkyl; R^(17a) represents hydrogen; R^(17b) represents C₁₋₄alkyl substituted with one —O—C₁₋₄alkyl substituent; and the pharmaceutically acceptable addition salts, and the solvates thereof.

The present invention relates in particular to compounds of Formula (I) as defined herein, tautomers and stereoisomeric forms thereof, wherein

R¹ represents C₁₋₄alkyl;

R² represents C₁₋₆alkyl substituted with one R⁵;

Y represents CR⁴;

R⁴ represents hydrogen;

R⁵ represents —OR⁷;

R⁷ represents hydrogen;

R³ represents 2-oxo-1,2-dihydropyridin-3-yl,

wherein said 2-oxo-1,2-dihydropyridin-3-yl may optionally substituted on the N-atom with a substituent selected from the group consisting of C₁₋₆alkyl; C₁₋₄alkyl substituted with one, two or three —OH substituents; C₁₋₄alkyl substituted with one R¹³; C₁₋₄alkyl substituted with one R¹⁸; and wherein said 2-oxo-1,2-dihydropyridin-3-yl may optionally be substituted on the ring carbon atoms with in total one, two or three substituents each independently selected from the group consisting of halo; C₁₋₆alkyl; and Het^(1a); R¹⁸ represents a 5-membered aromatic ring containing one, two or three N-atoms; wherein said 5-membered aromatic ring may optionally be substituted with one substituent selected from the group consisting of C₁₋₄alkyl and C₃₋₆cycloalkyl; Het^(1a) and Het^(1d) each independently represents a 4- to 7-membered monocyclic saturated heterocyclyl containing one or two heteroatoms each independently selected from O and N; wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted, where possible, on one or two ring N-atoms with C₁₋₄alkyl; and wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted on one or two ring C-atoms with one or two substituents each independently selected from the group consisting of halo and C₁₋₄alkyl; R¹³ represents —O—C₁₋₄alkyl, —C(═O)NR^(15a)R^(15b), C₃₋₆cycloalkyl, or Het^(1d); R^(15a) represents C₁₋₄alkyl; R^(15b) represents C₁₋₄alkyl; and the pharmaceutically acceptable addition salts, and the solvates thereof.

The present invention relates in particular to compounds of Formula (I) as defined herein, tautomers and stereoisomeric forms thereof, wherein

R¹ represents C₁₋₄alkyl;

R² represents C₁₋₆alkyl substituted with one R⁵;

Y represents CR⁴;

R⁴ represents hydrogen;

R⁵ represents —OR⁷;

R⁷ represents hydrogen;

R³ represents 2-oxo-1,2-dihydropyridin-3-yl,

wherein said 2-oxo-1,2-dihydropyridin-3-yl may optionally substituted on the N-atom with a substituent selected from the group consisting of C₁₋₆alkyl; C₁₋₄alkyl substituted with one, two or three —OH substituents; C₁₋₄alkyl substituted with one R¹³; C₁₋₄alkyl substituted with one R¹⁸; and wherein said 2-oxo-1,2-dihydropyridin-3-yl may optionally be substituted on the ring carbon atoms with in total one, two or three substituents each independently selected from the group consisting of halo and C₁₋₆alkyl; R¹⁸ represents a 5-membered aromatic ring containing one, two or three N-atoms; wherein said 5-membered aromatic ring may optionally be substituted with one substituent selected from the group consisting of C₁₋₄alkyl and C₃₋₆cycloalkyl; Het^(1d) represents a 4- to 7-membered monocyclic saturated heterocyclyl containing one or two heteroatoms each independently selected from O and N; wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted on one or two ring C-atoms with one or two substituents each independently selected from the group consisting of halo and C₁₋₄alkyl; R¹³ represents —O—C₁₋₄alkyl, —C(═O)NR^(15a)R^(15b), C₃₋₆cycloalkyl, or Het^(1d); R^(15a) represents C₁₋₄alkyl; R^(15b) represents C₁₋₄alkyl; and the pharmaceutically acceptable addition salts, and the solvates thereof.

The present invention relates in particular to compounds of Formula (I) as defined herein, tautomers and stereoisomeric forms thereof, wherein

R¹ represents C₁₋₄alkyl;

R² represents C₁₋₆alkyl substituted with one R⁵;

Y represents CR⁴;

R⁴ represents hydrogen;

R⁵ represents —OR⁷;

R⁷ represents hydrogen;

R³ represents 2-oxo-1,2-dihydropyridin-3-yl,

wherein said 2-oxo-1,2-dihydropyridin-3-yl may optionally substituted on the N-atom with a substituent selected from the group consisting of C₁₋₆alkyl; C₁₋₄alkyl substituted with one R¹³; C₁₋₄alkyl substituted with one R¹⁸; and

wherein said 2-oxo-1,2-dihydropyridin-3-yl may optionally be substituted on the ring carbon atoms with in total one, two or three substituents each independently selected from the group consisting of halo and C₁₋₆alkyl;

R¹⁸ represents a 5-membered aromatic ring containing one, two or three N-atoms; wherein said 5-membered aromatic ring may optionally be substituted with one C₁₋₄alkyl substituent;

Het^(1d) represents a 4- to 7-membered monocyclic saturated heterocyclyl containing one or two heteroatoms each independently selected from O and N;

wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted on one or two ring C-atoms with one or two substituents each independently selected from the group consisting of halo and C₁₋₄alkyl;

R¹³ represents Het^(1d);

and the pharmaceutically acceptable addition salts, and the solvates thereof.

The present invention relates in particular to compounds of Formula (I) as defined herein, tautomers and stereoisomeric forms thereof, wherein

R¹ represents C₁₋₄alkyl;

R² represents C₁₋₆alkyl substituted with one R⁵;

Y represents CR⁴;

R⁴ represents hydrogen;

R⁵ represents —OR⁷;

R⁷ represents hydrogen;

R³ represents 2-oxo-1,2-dihydropyridin-3-yl,

wherein said 2-oxo-1,2-dihydropyridin-3-yl may optionally substituted on the N-atom with a substituent selected from the group consisting of C₁₋₆alkyl; C₁₋₄alkyl substituted with one R¹⁸; and

wherein said 2-oxo-1,2-dihydropyridin-3-yl may optionally be substituted on the ring carbon atoms with in total one, two or three substituents each independently selected from the group consisting of halo and C₁₋₆alkyl;

R¹⁸ represents a 5-membered aromatic ring containing one, two or three N-atoms; wherein said 5-membered aromatic ring may optionally be substituted with one C₁₋₄alkyl substituent;

and the pharmaceutically acceptable addition salts, and the solvates thereof.

The present invention relates in particular to compounds of Formula (I) as defined herein, tautomers and stereoisomeric forms thereof, wherein

R¹ represents C₁₋₄alkyl;

R² represents C₁₋₆alkyl substituted with one R⁵;

Y represents CR⁴;

R⁴ represents hydrogen;

R⁵ represents —OR⁷;

R⁷ represents hydrogen;

R³ represents 2-oxo-1,2-dihydropyridin-3-yl,

wherein said 2-oxo-1,2-dihydropyridin-3-yl may optionally substituted on the N-atom with a substituent selected from the group consisting of C₁₋₆alkyl; C₁₋₄alkyl substituted with one R¹³; C₁₋₄alkyl substituted with one R¹⁸; and

wherein said 2-oxo-1,2-dihydropyridin-3-yl may optionally be substituted on the ring carbon atoms with in total one, two or three substituents each independently selected from the group consisting of halo and C₁₋₆alkyl;

R¹⁸ represents

wherein the NH moiety is substituted with C₁₋₄alkyl; Het^(1d) represents 1-morpholinyl; R¹³ represents Het^(1d); and the pharmaceutically acceptable addition salts, and the solvates thereof.

The present invention relates in particular to compounds of Formula (I) as defined herein, tautomers and stereoisomeric forms thereof, wherein

R¹ represents C₁₋₄alkyl;

R² represents C₁₋₆alkyl substituted with one R⁵;

Y represents CR⁴;

R⁴ represents hydrogen;

R⁵ represents —OR⁷;

R⁷ represents hydrogen;

R³ represents 2-oxo-1,2-dihydropyridin-3-yl,

wherein said 2-oxo-1,2-dihydropyridin-3-yl may optionally substituted on the N-atom with a substituent selected from the group consisting of C₁₋₆alkyl; C₁₋₄alkyl substituted with one R¹⁸; and

wherein said 2-oxo-1,2-dihydropyridin-3-yl may optionally be substituted on the ring carbon atoms with in total one, two or three substituents each independently selected from the group consisting of halo and C₁₋₆alkyl;

R¹⁸ represents

wherein the NH moiety is substituted with C₁₋₄alkyl; and the pharmaceutically acceptable addition salts, and the solvates thereof.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein

R⁵ represents —NR^(6a)R^(6b), or —OR⁷;

R^(6b) represents hydrogen; C₁₋₄alkyl; C₃₋₆cycloalkyl; —C(═O)—C₁₋₄alkyl; —S(═O)₂—C₁₋₄alkyl; —C(═O)—C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —NR^(16a)R^(16b); or C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —S(═O)₂—C₁₋₄alkyl; R⁷ represents hydrogen, C₁₋₄alkyl, —C₁₋₄alkyl-NR^(8a)R^(8b), —C(═O)—R⁹, —S(═O)₂—OH, —P(═O)₂—OH, or —(C═O)—CH(NH₂)—C₁₋₄alkyl-Ar¹.

Another embodiment of the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments wherein R³ represents a 6-membered heteroaromatic ring containing 1 or 2 N-atoms, optionally substituted as mentioned in any of the other embodiments, wherein Y represents CR⁴ or N, in particular wherein Y represents CR⁴; and

wherein one or more of the following restrictions apply:

(a) R^(6b) represents C₁₋₄alkyl; C₃₋₆cycloalkyl; —C(═O)—C₁₋₄alkyl; or C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —S(═O)₂—C₁₋₄alkyl;

(b) R⁷ represents hydrogen, C₁₋₄alkyl, —C₁₋₄alkyl-NR^(8a)R^(8b), —C(═O)—R⁹, or —C₁₋₄alkyl-Het^(3b);

(c) R^(8a) represents hydrogen;

(d) R^(8b) represents C₁₋₄alkyl, or C₃₋₆cycloalkyl;

(e) R⁹ represents C₁₋₄alkyl, or C₁₋₄alkyl substituted with one substituent selected from the group consisting of —NH₂;

(f) R³ represents a 6-membered heteroaromatic ring containing 1 or 2 N-atoms, optionally substituted with one, two or three substituents each independently selected from the group consisting of halo; cyano; C₁₋₆alkyl; —O—C₁₋₄alkyl; —C(═O)—R¹⁰; —O—C₁₋₄alkyl-R¹²; C₃₋₆cycloalkyl; —O—C₃₋₆cycloalkyl; Het^(1a); —O-Het^(1b); C₁₋₄alkyl substituted with one, two or three —OH substituents; R¹⁸; R²¹; —P(═O)—(C₁₋₄alkyl)₂; —NR^(7a)R^(17b); C₁₋₄alkyl substituted with one, two or three halo atoms; C₁₋₄alkyl substituted with one R¹³; C₂₋₆alkenyl; and C₂₋₆alkenyl substituted with one R¹³; in particular, R³ represents a 6-membered heteroaromatic ring containing 1 or 2 N-atoms, optionally substituted with one, two or three substituents each independently selected from the group consisting of halo; cyano; C₁₋₆alkyl; —O—C₁₋₄alkyl; —C(═O)—R¹⁰; —O—C₁₋₄alkyl-R¹²; C₃₋₆cycloalkyl; —O—C₃₋₆cycloalkyl; Het^(1a); —O-Het^(1b); R¹⁸; R²¹; —P(═O)—(C₁₋₄alkyl)₂; —NR^(17a)R^(17b); C₁₋₄alkyl substituted with one, two or three halo atoms; C₁₋₄alkyl substituted with one R¹³; C₂₋₆alkenyl; and C₂₋₆alkenyl substituted with one R¹³; (g) R¹⁰ represents —O—C₁₋₄alkyl, —NR^(11a)R^(11b) or Het²; (h) R¹⁸ represents a 5-membered aromatic ring containing one, two or three N-atoms; wherein said 5-membered aromatic ring may optionally be substituted with one C₁₋₄alkyl substituent; (i) R²¹ represents 3,6-dihydro-2H-pyran-4-yl; (j) Het^(1a), Het^(1c) and Het^(1d) each independently represents a 4- to 7-membered monocyclic saturated heterocyclyl containing one or two heteroatoms each independently selected from O and N; wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted, where possible, on one or two ring N-atoms with a substituent each independently selected from the group consisting of C₁₋₄alkyl, C₃₋₆cycloalkyl, and C₁₋₄alkyl substituted with one —OH substituent; and wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted on one, two or three ring C-atoms with one or two substituents each independently selected from the group consisting of halo and C₁₋₄alkyl; in particular Het^(1a) and Het¹c each independently represents a 4- to 7-membered monocyclic saturated heterocyclyl containing one or two heteroatoms each independently selected from O and N; wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted, where possible, on one or two ring N-atoms with a substituent each independently selected from the group consisting of C₁₋₄alkyl, and C₁₋₄alkyl substituted with one —OH substituent; and wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted on one, two or three ring C-atoms with one or two C₁₋₄alkyl substituents; (k) Het^(1b) represents a 4- to 7-membered monocyclic saturated heterocyclyl, attached to the remainder of the molecule of Formula (I) through any available ring carbon atom, said Het^(1b) containing one or two heteroatoms each independently selected from O and N; wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted, where possible, on one or two ring N-atoms with a substituent each independently selected from the group consisting of C₁₋₄alkyl and C₃₋₆cycloalkyl; wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted on one, two or three ring C-atoms with one or two halo substituents; in particular Het^(1b) represents a 4- to 7-membered monocyclic saturated heterocyclyl, attached to the remainder of the molecule of Formula (I) through any available ring carbon atom, said Het^(1b) containing one or two heteroatoms each independently selected from O and N; wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted, where possible, on one or two ring N-atoms with a C₁₋₄alkyl substituent; (l) Het² represents a heterocyclyl of formula (b-1):

(b-1) represents a N-linked 4- to 7-membered monocyclic saturated heterocyclyl optionally containing one additional N-atom; wherein in case (b-1) contains one additional N-atom, said one N-atom may optionally be substituted with C₁₋₄alkyl; wherein (b-1) may optionally be substituted on one, two or three ring C-atoms with one or two —OH substituents; in particular Het² represents a heterocyclyl of formula (b-1):

(b-1) represents a N-linked 4- to 7-membered monocyclic saturated heterocyclyl optionally containing one additional N-atom; wherein in case (b-1) contains one additional N-atom, said one N-atom may optionally be substituted with C₁₋₄alkyl; (m) R^(11b) represents C₁₋₄alkyl; (n) R¹³ represents —O—C₁₋₄alkyl, —C(═O)NR^(15a)R^(15b), —NR^(19a)R^(19b), C₃₋₆cycloalkyl, or Het^(1d); in particular R¹³ represents —O—C₁₋₄alkyl, —C(═O)NR^(15a)R^(15b), or C₃₋₆cycloalkyl; (o) R¹² represents —OH, —O—C₁₋₄alkyl, —C(═O)NR^(14c)R^(14d), C₃₋₆cycloalkyl, or Het^(1c); (p) Het^(3a) and Het^(3b) each independently represents a heterocyclyl of formula (c-1):

(c-1) represents a N-linked 4- to 7-membered monocyclic saturated heterocyclyl optionally containing one additional heteroatom selected from O and N; (q) R^(11a), R^(14c), R^(15a), R^(17a) each independently represents hydrogen or C₁₋₄alkyl; (r) R^(14d), R^(15b), R^(17b) and R^(19b) each independently represents C₁₋₄alkyl; C₃₋₆cycloalkyl; or C₁₋₄alkyl substituted with one —O—C₁₋₄alkyl substituent; in particular R^(14d), R^(15b), R^(17b) each independently represents C₁₋₄alkyl; or C₁₋₄alkyl substituted with one —O—C₁₋₄alkyl substituent.

Another embodiment of the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments wherein R³ represents a 6-membered heteroaromatic ring containing 1 or 2 N-atoms, optionally substituted as mentioned in any of the other embodiments, wherein Y represents CR⁴ or N, in particular wherein Y represents CR⁴; and wherein one or more of the following restrictions apply:

(a) R² represents C₁₋₆alkyl substituted with one R⁵;

(b) R⁵ represents —NR^(6a)R^(6b), or —OR⁷;

(c) R^(6a) represents hydrogen;

(d) R^(6b) represents —C(═O)—C₁₋₄alkyl;

(e) R⁷ represents hydrogen;

(f) R³ represents a 6-membered heteroaromatic ring containing 1 or 2 N-atoms, optionally substituted with one, two or three substituents each independently selected from the group consisting of halo; cyano; C₁₋₆alkyl; —O—C₁₋₄alkyl; —C(═O)—R¹⁰; —O—C₁₋₄alkyl-R¹²; Het^(1a); —NR^(17a)R^(17b); C₁₋₄alkyl substituted with one R¹³; (g) R¹⁰ represents —NR^(11a)R^(11b); (h) Het^(1a) represents a 4- to 7-membered monocyclic saturated heterocyclyl containing one or two heteroatoms each independently selected from O and N; wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted, where possible, on one or two ring N-atoms with a substituent each independently selected from the group consisting of C₁₋₄alkyl, and C₁₋₄alkyl substituted with one —OH substituent; (i) R^(11b) represents C₁₋₄alkyl; (j) R¹³ represents —O—C₁₋₄alkyl; (k) R¹² represents —O—C₁₋₄alkyl; (l) R^(7a) represents hydrogen; (m) R^(17b) represents C₁₋₄alkyl substituted with one —O—C₁₋₄alkyl substituent.

Another embodiment of the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments wherein R³ represents 2-oxo-1,2-dihydropyridin-3-yl, optionally substituted as mentioned in any of the other embodiments, wherein Y represents CR⁴ or N, in particular wherein Y represents CR⁴; and wherein one or more of the following restrictions apply:

(a) R¹ represents C₁₋₄alkyl;

(b) R² represents C₁₋₆alkyl substituted with one R⁵;

(c) R⁴ represents hydrogen;

(d) R⁵ represents Het³a, —NR^(6a)R^(6b), or —OR⁷; in particular R⁵ represents —OR⁷;

(e) R⁷ represents hydrogen, C₁₋₄alkyl, —C₁₋₄alkyl-NR^(8a)R^(8b), —C(═O)—R⁹, or —C₁₋₄alkyl-Het^(3b); in particular R⁷ represents hydrogen;

(f) R³ represents 2-oxo-1,2-dihydropyridin-3-yl,

wherein said 2-oxo-1,2-dihydropyridin-3-yl may optionally substituted on the N-atom with a substituent selected from the group consisting of C₁₋₆alkyl; C₁₋₄alkyl substituted with one, two or three —OH substituents; C₁₋₄alkyl substituted with one R¹³; C₁₋₄alkyl substituted with one R¹⁸; and wherein said 2-oxo-1,2-dihydropyridin-3-yl may optionally be substituted on the ring carbon atoms with in total one, two or three substituents each independently selected from the group consisting of halo; C₁₋₆alkyl; —C(═O)—R¹⁰; and Het^(1a); in particular R³ represents 2-oxo-1,2-dihydropyridin-3-yl, wherein said 2-oxo-1,2-dihydropyridin-3-yl may optionally substituted on the N-atom with a substituent selected from the group consisting of C₁₋₆alkyl; C₁₋₄alkyl substituted with one, two or three —OH substituents; C₁₋₄alkyl substituted with one R¹³; C₁₋₄alkyl substituted with one R¹⁸; and wherein said 2-oxo-1,2-dihydropyridin-3-yl may optionally be substituted on the ring carbon atoms with in total one, two or three substituents each independently selected from the group consisting of halo; C₁₋₆alkyl; and Het^(1a); (g) R¹⁸ represents a 5-membered aromatic ring containing one, two or three N-atoms; wherein said 5-membered aromatic ring may optionally be substituted with one substituent selected from the group consisting of C₁₋₄alkyl and C₃₋₆cycloalkyl; (h) Het^(1a), Het^(1e) and Het^(1d) each independently represents a 4- to 7-membered monocyclic saturated heterocyclyl containing one or two heteroatoms each independently selected from O and N; wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted, where possible, on one or two ring N-atoms with a substituent each independently selected from the group consisting of C₁₋₄alkyl, C₃₋₆cycloalkyl, and C₁₋₄alkyl substituted with one —OH substituent; and wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted on one, two or three ring C-atoms with one or two substituents each independently selected from the group consisting of halo and C₁₋₄alkyl; in particular Het^(1a) and Het^(1d) each independently represents a 4- to 7-membered monocyclic saturated heterocyclyl containing one or two heteroatoms each independently selected from O and N; wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted, where possible, on one or two ring N-atoms with C₁₋₄alkyl; and wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted on one or two ring C-atoms with one or two substituents each independently selected from the group consisting of halo and C₁₋₄alkyl; (i) R¹³ represents —O—C₁₋₄alkyl, —C(═O)NR^(15a)R^(15b), —NR^(19a)R^(19b), C₃₋₆cycloalkyl, or Het^(1d); in particular R¹³ represents —O—C₁₋₄alkyl, —C(═O)NR^(15a)R^(15b), C₃₋₆cycloalkyl, or Het^(11d) (j) R^(15a) represents C₁₋₄alkyl; (k) R^(15b) represents C₁₋₄alkyl; C₃₋₆cycloalkyl; or C₁₋₄alkyl substituted with one —O—C₁₋₄alkyl substituent; in particular R^(15b) represents C₁₋₄alkyl.

Another embodiment of the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments wherein R³ represents 2-oxo-1,2-dihydropyridin-3-yl, optionally substituted as mentioned in any of the other embodiments, wherein Y represents CR⁴ or N, in particular wherein Y represents CR⁴; and wherein one or more of the following restrictions apply:

(a) R¹ represents C₁₋₄alkyl;

(b) R² represents C₁₋₆alkyl substituted with one R⁵;

(c) R⁴ represents hydrogen;

(d) R⁵ represents —OR⁷;

(e) R⁷ represents hydrogen;

(f) R³ represents 2-oxo-1,2-dihydropyridin-3-yl,

wherein said 2-oxo-1,2-dihydropyridin-3-yl may optionally substituted on the N-atom with a substituent selected from the group consisting of C₁₋₆alkyl; C₁₋₄alkyl substituted with one R¹³; C₁₋₄alkyl substituted with one R¹⁸; and

wherein said 2-oxo-1,2-dihydropyridin-3-yl may optionally be substituted on the ring carbon atoms with in total one, two or three substituents each independently selected from the group consisting of halo and C₁₋₆alkyl;

(g) R¹⁸ represents a 5-membered aromatic ring containing one, two or three N-atoms; wherein said 5-membered aromatic ring may optionally be substituted with one C₁₋₄alkyl substituent;

(h) Het^(1d) represents a 4- to 7-membered monocyclic saturated heterocyclyl containing one or two heteroatoms each independently selected from O and N;

wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted on one or two ring C-atoms with one or two substituents each independently selected from the group consisting of halo and C₁₋₄alkyl;

(i) R¹³ represents Het^(1d)

In an embodiment, the present invention relates to a subgroup of Formula (I), hereby named compounds of Formula (I′), and the pharmaceutically acceptable addition salts, and the solvates thereof:

wherein R¹ represents C₁₋₄alkyl; R² represents C₁₋₆alkyl substituted with one R⁵; in particular wherein R¹ represents C₁₋₄alkyl; R² represents C₁₋₆alkyl substituted with one R⁵; R⁵ represents —OR⁷; more in particular wherein R¹ represents C₁₋₄alkyl; R² represents C₁₋₆alkyl substituted with one R⁵; R⁵ represents —OR⁷; R⁷ represents hydrogen; and wherein all other variables are defined according to any of the other embodiments.

In an embodiment, the present invention relates to a subgroup of Formula (I), hereby named compounds of Formula (I″), and the pharmaceutically acceptable addition salts, and the solvates thereof:

wherein R¹ represents C₁₋₄alkyl; R² represents C₁₋₆alkyl substituted with one R⁵; in particular wherein R¹ represents C₁₋₄alkyl; R² represents C₁₋₆alkyl substituted with one R⁵; R⁵ represents —OR⁷; more in particular wherein R¹ represents C₁₋₄alkyl; R² represents C₁₋₆alkyl substituted with one R⁵; R⁵ represents —OR⁷; R⁷ represents hydrogen; and wherein all other variables are defined according to any of the other embodiments.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein

R¹ represents methyl;

R² represents methyl or —CH₂—OH.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein

R¹ represents methyl; R² represents —CH₂—OH.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R³ represents pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl, each of which may optionally be substituted according to any of the other embodiments;

in particular R³ represents 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 5-pyrimidinyl, 4-pyrimidinyl, 4-pyridazinyl or 2-pyrazinyl, each of which may optionally be substituted according to any of the other embodiments.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R³ represents pyridinyl, pyrimidinyl or pyridazinyl, each of which may optionally be substituted according to any of the other embodiments;

in particular R³ represents 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 5-pyrimidinyl, 4-pyrimidinyl, or 4-pyridazinyl, each of which may optionally be substituted according to any of the other embodiments.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R³ represents a 6-membered heteroaromatic ring containing 1 or 2 N-atoms, substituted with one, two or three substituents according to any of the other embodiments, provided however that the substituents are not selected from the group consisting of —S(═O)₂—C₁₋₄alkyl; —S(═O)(═N—R^(20a))—C₁₋₄alkyl; and —P(═O)—(C₁₋₄alkyl)₂.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein

R³ represents 2-oxo-1,2-dihydropyridin-3-yl optionally substituted according to any of the other embodiments, provided however that the substituents on the carbon atoms are not selected from the group consisting of

—S(═O)₂—C₁₋₄alkyl; —S(═O)(═N—R^(20a))—C₁₋₄alkyl; and —P(═O)—(C₁₋₄alkyl)₂.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R⁴ is hydrogen or fluoro.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R⁴ is hydrogen.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R⁷ represents hydrogen.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein

R⁵ represents —OR⁷; and

R⁷ represents hydrogen.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein

R⁹ represents C₁₋₄alkyl, or C₁₋₄alkyl substituted with one substituent selected from the group consisting of —NH₂, —COOH, and Het⁶;

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R¹⁸ is attached to the remainder of the molecule of Formula (I) via a carbon atom.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R¹⁸ represents

in particular

each optionally substituted on carbon and/or nitrogen atoms according to any of the other embodiments.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R¹⁸ represents

optionally substituted on carbon and/or nitrogen atoms according to any of the other embodiments.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R¹⁸ represents

in particular

each substituted on the NH with C₁₋₄alkyl.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R¹⁸ represents

substituted on the NH with C₁₋₄alkyl.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het^(1a), Het^(1c) and Het^(1d) each independently represents morpholinyl, piperidinyl, pyrrolidinyl, oxetanyl, azetidinyl, piperazinyl, tetrahydro-2H-pyranyl, tetrahydrofuranyl, or hexahydro-1,4-oxazepinyl,

each optionally substituted on carbon and/or nitrogen atoms according to any of the other embodiments.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments wherein R³ represents a 6-membered heteroaromatic ring containing 1 or 2 N-atoms, optionally substituted as mentioned in any of the other embodiments, wherein Het^(1a), Het^(1c) and Het^(1d) each independently represents morpholinyl, piperidinyl, oxetanyl, piperazinyl, tetrahydro-2H-pyranyl, or tetrahydrofuranyl,

each optionally substituted on carbon and/or nitrogen atoms according to any of the other embodiments.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments wherein R³ represents a 6-membered heteroaromatic ring containing 1 or 2 N-atoms, optionally substituted as mentioned in any of the other embodiments, wherein Het^(1a), Het^(1c) and Het^(1d) each independently represents

each optionally substituted on carbon and/or nitrogen atoms according to any of the other embodiments.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments wherein R³ represents a 6-membered heteroaromatic ring containing 1 or 2 N-atoms, optionally substituted as mentioned in any of the other embodiments, wherein Het^(1a) represents

each optionally substituted on carbon and/or nitrogen atoms according to any of the other embodiments.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments wherein R³ represents a 6-membered heteroaromatic ring containing 1 or 2 N-atoms, optionally substituted as mentioned in any of the other embodiments, and wherein Het^(1c) represents

each optionally substituted on carbon and/or nitrogen atoms according to any of the other embodiments.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments wherein R³ represents a 6-membered heteroaromatic ring containing 1 or 2 N-atoms, optionally substituted as mentioned in any of the other embodiments, and wherein Het^(1d) represents

each optionally substituted on carbon and/or nitrogen atoms according to any of the other embodiments.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments wherein R³ represents 2-oxo-1,2-dihydropyridin-3-yl, optionally substituted as mentioned in any of the other embodiments, and wherein Het^(1a), Het^(1c) and Het^(1d) each independently represents morpholinyl, piperidinyl, pyrrolidinyl, oxetanyl, azetidinyl, piperazinyl, tetrahydro-2H-pyranyl, or hexahydro-1,4-oxazepinyl,

each optionally substituted on carbon and/or nitrogen atoms according to any of the other embodiments.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments wherein R³ represents 2-oxo-1,2-dihydropyridin-3-yl, optionally substituted as mentioned in any of the other embodiments, and wherein Het^(1a), Het^(1c) and Het^(1d) each independently represents

each optionally substituted on carbon and/or nitrogen atoms according to any of the other embodiments.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments wherein R³ represents 2-oxo-1,2-dihydropyridin-3-yl, optionally substituted as mentioned in any of the other embodiments, and wherein Het^(1a), Het^(1c) and Het^(1d) each independently represents

each optionally substituted on carbon and/or nitrogen atoms according to any of the other embodiments.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments wherein R³ represents 2-oxo-1,2-dihydropyridin-3-yl, optionally substituted as mentioned in any of the other embodiments, and wherein Het^(1a) represents

optionally substituted on carbon and/or nitrogen atoms according to any of the other embodiments.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments wherein R³ represents 2-oxo-1,2-dihydropyridin-3-yl, optionally substituted as mentioned in any of the other embodiments, and wherein Het^(1c) represents

each optionally substituted on carbon and/or nitrogen atoms according to any of the other embodiments.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments wherein R³ represents 2-oxo-1,2-dihydropyridin-3-yl, optionally substituted as mentioned in any of the other embodiments, and wherein Het^(1d) represents

each optionally substituted on carbon and/or nitrogen atoms according to any of the other embodiments.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het^(1b), Het^(1e), Het^(1g) and Het⁴ each independently represents morpholinyl, piperidinyl, pyrrolidinyl, oxetanyl, azetidinyl, piperazinyl, tetrahydro-2H-pyranyl, tetrahydrofuranyl, or hexahydro-1,4-oxazepinyl, attached to the remainder of the molecule of Formula (I) through any available ring carbon atom,

each optionally substituted on carbon and/or nitrogen atoms according to any of the other embodiments.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments wherein R³ represents a 6-membered heteroaromatic ring containing 1 or 2 N-atoms, optionally substituted as mentioned in any of the other embodiments, and wherein Het^(1b), Het^(1e), Het^(1g) and Het⁴ each independently represents piperidinyl, tetrahydro-2H-pyranyl, or tetrahydrofuranyl, attached to the remainder of the molecule of Formula (I) through any available ring carbon atom,

each optionally substituted on carbon and/or nitrogen atoms according to any of the other embodiments.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R³ represents a 6-membered heteroaromatic ring containing 1 or 2 N-atoms, optionally substituted as mentioned in any of the other embodiments, and wherein Het^(1b), Het^(1e), Het^(1g) and Het⁴ each independently represents

each optionally substituted on carbon and/or nitrogen atoms according to any of the other embodiments.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments wherein R³ represents 2-oxo-1,2-dihydropyridin-3-yl, optionally substituted as mentioned in any of the other embodiments, and wherein Het^(1b), Het^(1e), Het^(1g) and Het⁴ each independently represents piperidinyl, tetrahydro-2H-pyranyl, or pyrrolidinyl, attached to the remainder of the molecule of Formula (I) through any available ring carbon atom,

each optionally substituted on carbon and/or nitrogen atoms according to any of the other embodiments.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments wherein R³ represents 2-oxo-1,2-dihydropyridin-3-yl, optionally substituted as mentioned in any of the other embodiments, and wherein Het^(1b), Het^(1e), Het^(1g) and Het⁴ each independently represents

each optionally substituted on carbon and/or nitrogen atoms according to any of the other embodiments.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het^(1g) represents

optionally substituted on carbon and/or nitrogen atoms according to any of the other embodiments.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het^(1e) represents

each optionally substituted on carbon and/or nitrogen atoms according to any of the other embodiments.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments wherein R³ represents a 6-membered heteroaromatic ring containing 1 or 2 N-atoms, optionally substituted as mentioned in any of the other embodiments, and wherein Het^(1b) represents

each optionally substituted on carbon and/or nitrogen atoms according to any of the other embodiments.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments wherein R³ represents 2-oxo-1,2-dihydropyridin-3-yl, optionally substituted as mentioned in any of the other embodiments, and wherein Het^(1b) represents

each optionally substituted on carbon and/or nitrogen atoms according to any of the other embodiments.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het⁴ represents pyrrolidinyl, piperidinyl, tetrahydropyranyl, azetidinyl, or 1,1-dioxidethiopyranyl;

each optionally substituted on carbon and/or nitrogen atoms according to any of the other embodiments.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het² represents

each optionally substituted on carbon and/or nitrogen atoms according to any of the other embodiments.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R³ represents a 6-membered heteroaromatic ring containing 1 or 2 N-atoms, optionally substituted as mentioned in any of the other embodiments, and wherein Het² represents

optionally substituted on carbon and/or nitrogen atoms according to any of the other embodiments; in particular the hydrogen on the nitrogen atom is replaced by C₁₋₄alkyl.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het^(3a), Het^(3b), Het⁵, Het⁶ and Het^(1f) each independently represents

each optionally substituted on carbon and/or nitrogen atoms according to any of the other embodiments.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R³ represents 2-oxo-1,2-dihydropyridin-3-yl, optionally substituted as mentioned in any of the other embodiments.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Y represents CR⁴; and wherein R³ represents 2-oxo-1,2-dihydropyridin-3-yl, optionally substituted as mentioned in any of the other embodiments.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R³ represents a 6-membered heteroaromatic ring containing 1 or 2 N-atoms, optionally substituted as mentioned in any of the other embodiments.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Y represents CR⁴; and wherein R³ represents a 6-membered heteroaromatic ring containing 1 or 2 N-atoms, optionally substituted as mentioned in any of the other embodiments.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R³ represents a 6-membered heteroaromatic ring containing 1 or 2 N-atoms, optionally substituted as mentioned in any of the other embodiments, wherein Het^(3a) represents

each optionally substituted on carbon and/or nitrogen atoms according to any of the other embodiments.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R³ represents a 6-membered heteroaromatic ring containing 1 or 2 N-atoms, optionally substituted as mentioned in any of the other embodiments, and wherein Het^(3b) represents

each optionally substituted on carbon and/or nitrogen atoms according to any of the other embodiments.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het⁵ represents

each optionally substituted according to any of the other embodiments.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het⁶ represents

each optionally substituted on carbon and/or nitrogen atoms according to any of the other embodiments.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het^(1f) represents

each optionally substituted on carbon and/or nitrogen atoms according to any of the other embodiments.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het⁷ and Het⁸ each independently represent

optionally substituted on carbon atoms according to any of the other embodiments.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein

Het^(1a), Het^(1c) and Het^(1d) each independently represents a 4- to 7-membered monocyclic saturated heterocyclyl containing one or two heteroatoms each independently selected from O, S, S(═O)_(p) and N;

wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted, where possible, on one or two ring N-atoms with a substituent each independently selected from the group consisting of C₁₋₄alkyl, C₃₋₆cycloalkyl, and C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —O—C₁₋₄alkyl; and wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted on one, two or three ring C-atoms with one or two substituents each independently selected from the group consisting of —OH, halo, C₁₋₄alkyl, cyano, —C(═O)—C₁₋₄alkyl, —O—C₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)₂.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het² represents a heterocyclyl of formula (b-1):

(b-1) represents a N-linked 4- to 7-membered monocyclic saturated heterocyclyl optionally containing one additional heteroatom selected from O, S, S(═O)_(p) and N; wherein in case (b-1) contains one additional N-atom, said N-atom may optionally be substituted with C₁₋₄alkyl; and wherein (b-1) may optionally be substituted on one, two or three ring C-atoms with one or two substituents each independently selected from the group consisting of halo, —OH, cyano, C₁₋₄alkyl, —O—C₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, and C₁₋₄alkyl-OH.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein

Het^(1a) represents a 4- to 7-membered monocyclic saturated heterocyclyl containing one or two heteroatoms each independently selected from O, S, S(═O)_(p) and N; or a 6- to 11-membered bicyclic saturated heterocyclyl, including fused, spiro and bridged cycles, containing one, two or three heteroatoms each independently selected from O, S, S(═O)_(p) and N; wherein said 4- to 7-membered monocyclic saturated heterocyclyl or said 6- to 11-membered bicyclic saturated heterocyclyl may optionally be substituted, where possible, on one or two ring N-atoms with a substituent each independently selected from the group consisting of C₁₋₄alkyl, C₃₋₆cycloalkyl, and C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —O—C₁₋₄alkyl; and wherein said 4- to 7-membered monocyclic saturated heterocyclyl or said 6- to 11-membered bicyclic saturated heterocyclyl may optionally be substituted on one, two or three ring C-atoms with one or two substituents each independently selected from the group consisting of —OH, halo, C₁₋₄alkyl, cyano, —C(═O)—C₁₋₄alkyl, —O—C₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)₂; Het^(1c) and Het^(1d) each independently represents a 4- to 7-membered monocyclic saturated heterocyclyl containing one or two heteroatoms each independently selected from O, S, S(═O)_(p) and N; or in case Het^(1c) and Het^(1d) are attached to the remainder of the molecule of Formula (I) through an N-atom, Het^(1c) and Het^(1d) may also represent a N-linked 6- to 11-membered bicyclic saturated heterocyclyl, including fused, spiro and bridged cycles, optionally containing one or two additional heteroatoms each independently selected from O, S, S(═O)_(p) and N; wherein said 4- to 7-membered monocyclic saturated heterocyclyl or said N-linked 6- to 11-membered bicyclic saturated heterocyclyl may optionally be substituted, where possible, on one or two ring N-atoms with a substituent each independently selected from the group consisting of C₁₋₄alkyl, C₃₋₆cycloalkyl, and C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —O—C₁₋₄alkyl; and wherein said 4- to 7-membered monocyclic saturated heterocyclyl or said N-linked 6- to 11-membered bicyclic saturated heterocyclyl may optionally be substituted on one, two or three ring C-atoms with one or two substituents each independently selected from the group consisting of —OH, halo, C₁₋₄alkyl, cyano, —C(═O)—C₁₋₄alkyl, —O—C₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)₂.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Y represents CR⁴.

In an embodiment, the present invention relates to a subgroup of Formula (I), hereby named compounds of Formula (I-x), and the pharmaceutically acceptable addition salts, and the solvates thereof:

wherein all variables are defined according to any of the other embodiments.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Y represents N.

In an embodiment, the present invention relates to a subgroup of Formula (I), hereby named compounds of Formula (I-y), and the pharmaceutically acceptable addition salts, and the solvates thereof:

wherein all variables are defined according to any of the other embodiments.

In an embodiment, the present invention relates to a subgroup of Formula (I) as defined in the general reaction schemes.

In an embodiment the compound of Formula (I) is selected from the group consisting of compounds 3, 4, 6, 10, 33, 50, 59, 65, 93, 103, 115, 124, 140, 4i, 7i and 13i, tautomers and stereoisomeric forms thereof,

and the pharmaceutically acceptable addition salts, and the solvates thereof.

In an embodiment the compound of Formula (I) is selected from the group consisting of compounds 3, 4, 6, 10, 33, 50, 59, 65, 93, 103, 115, 124, 140, 4i, 7i and 13i.

In an embodiment the compound of Formula (I) is selected from the group consisting of any of the exemplified compounds,

tautomers and stereoisomeric forms thereof,

and the free bases, any pharmaceutically acceptable addition salts, and the solvates thereof.

All possible combinations of the above-indicated embodiments are considered to be embraced within the scope of this invention.

Methods for the Preparation of Compounds of Formula (I)

In this section, as in all other sections unless the context indicates otherwise, references to Formula (I) also include all other sub-groups and examples thereof as defined herein.

The general preparation of some typical examples of the compounds of Formula (I) is described hereunder and in the specific examples, and are generally prepared from starting materials which are either commercially available or prepared by standard synthetic processes commonly used by those skilled in the art. The following schemes are only meant to represent examples of the invention and are in no way meant to be a limit of the invention.

Alternatively, compounds of the present invention may also be prepared by analogous reaction protocols as described in the general schemes below, combined with standard synthetic processes commonly used by those skilled in the art of organic chemistry.

The skilled person will realise that functionalization reactions illustrated in the Schemes below for compounds of Formula (I) wherein Y is CR⁴, may also be carried out for compounds wherein Y is N. The skilled person will realise this applies, for example and without limitation, to steps 3 and 4 of scheme 2 and scheme 18.

The skilled person will realize that in the reactions described in the Schemes, although this is not always explicitly shown, it may be necessary to protect reactive functional groups (for example hydroxy, amino, or carboxy groups) where these are desired in the final product, to avoid their unwanted participation in the reactions. For example in Scheme 6, the NH moiety on the pyrimidinyl can be protected with a t-butoxycarbonyl protecting group. In general, conventional protecting groups can be used in accordance with standard practice. The protecting groups may be removed at a convenient subsequent stage using methods known from the art. This is illustrated in the specific examples.

The skilled person will realize that in the reactions described in the Schemes, it may be advisable or necessary to perform the reaction under an inert atmosphere, such as for example under N₂-gas atmosphere.

It will be apparent for the skilled person that it may be necessary to cool the reaction mixture before reaction work-up (refers to the series of manipulations required to isolate and purify the product(s) of a chemical reaction such as for example quenching, column chromatography, extraction).

The skilled person will realize that heating the reaction mixture under stirring may enhance the reaction outcome. In some reactions microwave heating may be used instead of conventional heating to shorten the overall reaction time.

The skilled person will realize that another sequence of the chemical reactions shown in the Schemes below, may also result in the desired compound of formula (I).

The skilled person will realize that intermediates and final compounds shown in the schemes below may be further functionalized according to methods well-known by the person skilled in the art.

In the general schemes below, R³ being a C-linked 6-membered heteroaromatic ring containing 1 or 2 N-atoms is represented as

In general, compounds of Formula (I) wherein R² is R^(2a) being C₁₋₆alkyl, Y is CR⁴, and wherein all the other variables are defined according to the scope of the present invention, hereby named compounds of Formula (Ia), can be prepared according to the following reaction Scheme 1. In Scheme 1 halo¹ is defined as Cl, Br or I; and PG¹ represents a suitable protecting group, such as for example tert-(butoxycarbonyl). All other variables in Scheme 1 are defined according to the scope of the present invention.

In Scheme 1, the following reaction conditions apply:

In general, compounds of Formula (I) wherein R² is R^(2a) being C₁₋₆alkyl, R³ is a C-linked 6-membered heteroaromatic ring containing 1 or 2 N-atoms, which is substituted with —C(═O)—R¹⁰ and optionally substituted with other substituents according to the scope of the present invention, Y is CR⁴, and wherein all the other variables are as defined according to the scope of the present invention, hereby named compounds of Formula (Ib), can be prepared according to the following reaction Scheme 2. In Scheme 2 halo¹ is defined as Cl, Br or I; PG¹ represents a suitable protecting group, such as for example tert-(butoxycarbonyl). All other variables in Scheme 2 are defined according to the scope of the present invention.

In Scheme 2, the following reaction conditions apply:

In general, compounds of Formula (I) wherein R² is R^(2a) being C₁₋₆alkyl, R³ is a 2-oxo-1,2-dihydropyridin-3-yl substituted with —C(═O)—R¹⁰ and optionally substituted with other substituents according to the scope of the present invention, Y is CR⁴, and wherein all the other variables are as defined according to the scope of the present invention, hereby named compounds of Formula (Ib-i), can be prepared according to the following reaction Scheme 2-i. In Scheme 2-i, X is defined as an optional substituent on the N-atom of the 2-oxo-1,2-dihydropyridin-3-yl (according to the scope), halo¹ is defined as Cl, Br or I; PG¹ represents a suitable protecting group, such as for example tert-(butoxycarbonyl). All other variables in Scheme 2-i are defined according to the scope of the present invention.

Scheme 2-i is shown below and the same reaction conditions as mentioned for Scheme 2 above apply:

In general, compounds of Formula (I) wherein R² is R^(2b) being C₁₋₆alkyl substituted with one OH, Y is CR⁴, and wherein all the other variables are as defined according to the scope of the present invention, hereby named compounds of Formula (Ic), can be prepared according to the following reaction Scheme 3. In Scheme 3 halo¹ is defined as Cl, Br or I; PG¹ represents a suitable protecting group, such as for example tert-(butoxycarbonyl) and PG² represents a suitable protecting group, such as for example tert-butyl-dimethylsilyl. All other variables in Scheme 3 are defined according to the scope of the present invention.

In Scheme 3, the following reaction conditions apply:

In general, compounds of Formula (I) wherein R² is R^(2b) being C₁₋₆alkyl substituted with one OH, Y is CR⁴, R³ is a C-linked 6-membered heteroaromatic ring containing 1 or 2 N-atoms, which is substituted with —C(═O)—R¹⁰ and optionally substituted with other substituents according to the scope of the present invention and wherein all the other variables are as defined according to the scope of the present invention, hereby named compounds of Formula (Id), can be prepared according to the following reaction Scheme 4. In Scheme 4 halo¹ is defined as Cl, Br or I; PG¹ represents a suitable protecting group, such as for example tert-(butoxycarbonyl) and PG² represents a suitable protecting group, such as for example tert-butyl-dimethylsilyl. All other variables in Scheme 4 are defined according to the scope of the present invention.

In Scheme 4, the following reaction conditions apply:

In general, compounds of Formula (I) wherein R² is R^(2b) being C₁₋₆alkyl substituted with one OH, R³ is 2-oxo-1,2-dihydropyridin-3-yl substituted with —C(═O)—R¹⁰ on a carbon atom and optionally substituted with other substituents according to the scope of the present invention, Y is CR⁴, and wherein all the other variables are as defined according to the scope of the present invention, hereby named compounds of Formula (Id-i), can be prepared according to the following reaction Scheme 4-i. In Scheme 4-i, X is defined as an optional subsistent on the N-atom of the 2-oxo-1,2-dihydropyridin-3-yl, halo¹ is defined as Cl, Br or I; PG¹ represents a suitable protecting group, such as for example tert-(butoxycarbonyl) and PG² represents a suitable protecting group, such as for example tert-butyl-dimethylsilyl. All other variables in Scheme 4-i are defined according to the scope of the present invention.

Scheme 4-i is shown below and the same reaction conditions as mentioned for Scheme 4 above apply:

In general, compounds of Formula (I) wherein R² is R^(2c) being C₁₋₆alkyl substituted with one Het^(3a) or —NR^(6a)R^(6b), wherein R^(6b) is R^(6ba) being H, C₁₋₄alkyl and C₃₋₆cycloalkyl, Y is CR⁴, and wherein all the other variables are as defined according to the scope of the present invention, hereby named compounds of Formula (Ie) and Formula (If), can be prepared according to the following reaction Scheme 5. In Scheme 5 PG¹ represents a suitable protecting group, such as for example tert-(butoxycarbonyl). All other variables in Scheme 5 are defined according to the scope of the present invention.

In Scheme 5, the following reaction conditions apply:

In general, compounds of Formula (I) wherein R² is C₁₋₆alkyl substituted with one OR^(7a), R^(7a) being —C(═O)—R⁹ or —(C═O)—CH(NH₂)—C₁₋₄alkyl-Ar¹), Y is CR⁴, and wherein all the other variables are as defined according to the scope of the present invention, hereby named compounds of Formula (Ig), can be prepared according to the following reaction Scheme 6. In Scheme 6 PG³ represents a suitable protecting group, such as for example a tert-(butoxycarbonyl), a tert-butyl or a benzyl. All other variables in Scheme 6 are defined according to the scope of the present invention.

In Scheme 6, the following reaction conditions apply:

In general, compounds of Formula (I) wherein R² is C₁₋₆alkyl substituted with one OR^(7b), R^(7b) being C₁₋₄alkyl, Y is CR⁴, and wherein all the other variables are as defined according to the scope of the present invention, hereby named compounds of Formula (Ih), can be prepared according to the following reaction Scheme 7. In Scheme 7 halo¹ is defined as Cl, Br or I; PG¹ represents a suitable protecting group, such as for example tert-(butoxycarbonyl) and PG² represents a suitable protecting group, such as for example tert-butyl-dimethylsilyl; W represents a leaving group, such as for example a methane sulfonate or toluene sulfonate or an halogen (Cl, Br or I). All other variables in Scheme 7 are defined according to the scope of the present invention.

In general, compounds of Formula (I) wherein R² is C₁₋₆alkyl substituted with one OR⁷, R^(7c) being C₁₋₄alkyl-NR^(8a)R^(8b) or C₁₋₄alkyl-Het^(3b), Y is CR⁴, and wherein all the other variables are as defined according to the scope of the present invention, hereby named compounds of Formula (Ii) and Formula (Ij), can be prepared according to the following reaction Scheme 8. In Scheme 8 halo¹ is defined as Cl, Br or I; PG¹ represents a suitable protecting group, such as for example tert-(butoxycarbonyl); W¹ represents a leaving group, such as for example a methane sulfonate or toluene sulfonate or an halogen (Cl, Br or I); W² represents a leaving group, such as for example a mesyl or a tosyl. All other variables in Scheme 8 are defined according to the scope of the present invention.

In Scheme 8, the following reaction conditions apply:

In general, intermediates of Formula (II) and (III) wherein R² is R^(2a) being C₁₋₆alkyl, and wherein all the other variables are as defined according to the scope of the present invention, hereby named compounds of Formula (II) and (III), can be prepared according to the following reaction Scheme 9. In Scheme 9 halo¹ is defined as Cl, Br, I; halo² is defined as Cl, Br, I; PG¹ represents a suitable protecting group, such as for example tert-(butoxycarbonyl); W¹ represents a leaving group, such as for example a methane sulfonate or toluene sulfonate or an halogen (Cl, Br or I). All other variables in Scheme 9 are defined according to the scope of the present invention.

In Scheme 9, the following reaction conditions apply:

In general, intermediates of Formula (XII) and (XIII) wherein R² is R^(2b) being C₁₋₆alkyl substituted with one OH, and wherein all the other variables are as defined according to the scope of the present invention, hereby named compounds of Formula (XII) and (XIII), can be prepared according to the following reaction Scheme 10. In Scheme 10 halo¹ is defined as Cl, Br, I; halo² is defined as Cl, Br, I; PG¹ represents a suitable protecting group, such as for example tert-(butoxycarbonyl) and PG² represents a suitable protecting group, such as for example tert-butyl-dimethylsilyl; W¹ represents a leaving group, such as for example a methane sulfonate or toluene sulfonate or an halogen (Cl, Br or I). All other variables in Scheme 10 are defined according to the scope of the present invention.

In Scheme 10, the following reaction conditions apply:

In general, compounds of Formula (I) wherein R² is as shown in the scheme 11, Y is CR⁴, and wherein all the other variables are as defined according to the scope of the present invention, hereby named compounds of Formula (Ik) can be prepared according to the following reaction Scheme 11. In Scheme 11 PG¹ represents a suitable protecting group, such as for example tert-(butoxycarbonyl). All other variables in Scheme 11 are defined according to the scope of the present invention.

In Scheme 11, the following reaction conditions apply:

In general, compounds of Formula (I) wherein R² is as shown in the scheme 12, Y is CR⁴, and wherein all the other variables are as defined according to the scope of the present invention, hereby named compounds of Formula (I1) can be prepared according to the following reaction Scheme 12. In Scheme 12 PG¹ represents a suitable protecting group, such as for example tert-(butoxycarbonyl). All other variables in Scheme 12 are defined according to the scope of the present invention.

In Scheme 12, the following reaction conditions apply:

In general, compounds of Formula (I) wherein R² is as shown in the scheme 13, Y is CR⁴, and wherein all the other variables are as defined according to the scope of the present invention, hereby named compounds of Formula (Im) can be prepared according to the following reaction Scheme 13. In Scheme 13 PG¹ represents a suitable protecting group, such as for example tert-(butoxycarbonyl). All other variables in Scheme 13 are defined according to the scope of the present invention.

In Scheme 13, the following reaction conditions apply:

In general, compounds of Formula (I) wherein R² is being C₁₋₆alkyl substituted with one Het^(3a) or —NR^(6a)R^(6b), wherein R^(6a) is being H, R^(6b) is being —C(═O)—C₁₋₄alkyl; —C(═O)-Het⁴; —S(═O)₂—C₁₋₄alkyl, Y is CR⁴, and wherein all the other variables are as defined according to the scope of the present invention, hereby named compounds of Formula (In), Formula (Io) and Formula (Ip), can be prepared according to the following reaction Scheme 14. In Scheme 14, PG¹ represents a suitable protecting group, such as for example tert-(butoxycarbonyl). All other variables in Scheme 14 are defined according to the scope of the present invention.

In Scheme 14, the following reaction conditions apply:

In general, compounds of Formula (I) wherein R² is being C₁₋₆alkyl substituted with one Het^(3a) or —NR^(6a)R^(6b), wherein R^(6a) is being C₁₋₄alkyl, R^(6b) is being —C(═O)—C₁₋₄alkyl; —C(═O)—Het⁴; —S(═O)₂—C₁₋₄alkyl, Y is CR⁴, and wherein all the other variables are as defined according to the scope of the present invention, hereby named compounds of Formula (Iq), Formula (Ir° and Formula (Is), can be prepared according to the following reaction Scheme 15. In Scheme 15, PG¹ represents a suitable protecting group, such as for example tert-(butoxycarbonyl). All other variables in Scheme 15 are defined according to the scope of the present invention.

In Scheme 15, the following reaction conditions apply:

In general, compounds of Formula (I) wherein R² is C₁₋₆alkyl substituted with one OR^(7d), R^(7d) being —S(═O)₂—OH or —P(═O)—(OH)₂, Y is CR⁴, and wherein all the other variables are as defined according to the scope of the present invention, hereby named compounds of Formula (It) and Formula (Iu), can be prepared according to the following reaction Scheme 16. All other variables in Scheme 16 are defined according to the scope of the present invention.

In Scheme 16, the following reaction conditions apply:

In general, intermediates of Formula (XII) wherein all the variables are as defined according to the scope of the present invention can be prepared according to the following reaction Scheme 17.

In Scheme 17, the following reaction conditions apply:

In general, compounds of Formula (I) wherein R² is C₁₋₆alkyl substituted with one R⁵, R⁵ being a fluorine, Y is CR⁴, and wherein all the other variables are as defined according to the scope of the present invention, hereby named compounds of Formula (Iv), can be prepared according to the following reaction Scheme 18. All other variables in Scheme 18 are defined according to the scope of the present invention.

In Scheme 18, the following reaction conditions apply:

In general, compounds of Formula (I) wherein R² is R^(2b) being C₁₋₆alkyl substituted with one OH, Y is N, and wherein all the other variables are as defined according to the scope of the present invention, hereby named compounds of Formula (Iw), can be prepared according to the following reaction Scheme 19. In Scheme 19, halo¹ is defined as Cl, Br or I; PG¹ represents a suitable protecting group, such as for example tert-(butoxycarbonyl) and PG² represents a suitable protecting group, such as for example tert-butyl-dimethylsilyl. All other variables in Scheme 19 are defined according to the scope of the present invention.

In Scheme 19, the following reaction conditions apply:

In general, compounds of Formula (I) wherein R² is R^(2b) being C₁₋₆alkyl substituted with one OH, R is a ring system according to the scope (represented as

in Scheme 20) substituted with —C(═O)—R¹⁰ and optionally substituted with other substituents according to the scope of the present invention, Y is CR⁴, and wherein all the other variables are as defined according to the scope of the present invention, hereby named compounds of Formula (Ida), (Idb) and (Idc) can be prepared according to the following reaction Scheme 20. In Scheme 20, halo¹ is defined as Cl, Br or I; PG¹ represents a suitable protecting group, such as for example tert-(butoxycarbonyl) and PG² represents a suitable protecting group, such as for example tert-butyl-dimethylsilyl. All other variables in Scheme 20 are defined according to the scope of the present invention.

In Scheme 20, the following reaction conditions apply:

In general, compounds of Formula (I) wherein R² is R^(2b) being C₁₋₆alkyl substituted with one OH, Y is CR⁴, and wherein all the other variables are as defined according to the scope of the present invention, hereby named compounds of Formula (Ic), can be prepared according to the following reaction Scheme 21. All other variables in Scheme 21 are defined according to the scope of the present invention or as above.

In Scheme 21, the following reaction conditions apply:

It will be appreciated that where appropriate functional groups exist, compounds of various formulae or any intermediates used in their preparation may be further derivatised by one or more standard synthetic methods employing condensation, substitution, oxidation, reduction, or cleavage reactions. Particular substitution approaches include conventional alkylation, arylation, heteroarylation, acylation, sulfonylation, halogenation, nitration, formylation and coupling procedures.

The compounds of Formula (I) may be synthesized in the form of racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures. The racemic compounds of Formula (I) containing a basic nitrogen atom may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali. An alternative manner of separating the enantiomeric forms of the compounds of Formula (I) involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically.

In the preparation of compounds of the present invention, protection of remote functionality (e.g., primary or secondary amine) of intermediates may be necessary. The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. Suitable amino-protecting groups (NH-Pg) include acetyl, trifluoroacetyl, t-butoxycarbonyl (Boc), benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). The need for such protection is readily determined by one skilled in the art. For a general description of protecting groups and their use, see T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 4th ed., Wiley, Hoboken, N.J., 2007.

Pharmacology

It has been found that the compounds of the present invention inhibit NF-κB-inducing kinase (NIK—also known as MAP3K14). Some of the compounds of the present invention may undergo metabolism to a more active form in vivo (prodrugs). Therefore the compounds according to the invention and the pharmaceutical compositions comprising such compounds may be useful for treating or preventing diseases such as cancer, inflammatory disorders, metabolic disorders including obesity and diabetes, and autoimmune disorders. In particular, the compounds according to the present invention and the pharmaceutical compositions thereof may be useful in the treatment of a haematological malignancy or solid tumour. In a specific embodiment said haematological malignancy is selected from the group consisting of multiple myeloma, non-Hodgkin's lymphoma, Hodgkin lymphoma, T-cell leukaemia, mucosa-associated lymphoid tissue lymphoma, diffuse large B-cell lymphoma and mantle cell lymphoma, in a particular embodiment mantle cell lymphoma. In another specific embodiment of the present invention, the solid tumour is selected from the group consisting of pancreatic cancer, breast cancer, melanoma and non-small cell lung cancer.

Examples of cancers which may be treated (or inhibited) include, but are not limited to, a carcinoma, for example a carcinoma of the bladder, breast, colon (e.g. colorectal carcinomas such as colon adenocarcinoma and colon adenoma), kidney, urothelial, uterus, epidermis, liver, lung (for example adenocarcinoma, small cell lung cancer and non-small cell lung carcinomas, squamous lung cancer), oesophagus, head and neck, gall bladder, ovary, pancreas (e.g. exocrine pancreatic carcinoma), stomach, gastrointestinal (also known as gastric) cancer (e.g. gastrointestinal stromal tumours), cervix, endometrium, thyroid, prostate, or skin (for example squamous cell carcinoma or dermatofibrosarcoma protuberans); pituitary cancer, a hematopoietic tumour of lymphoid lineage, for example leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, B-cell lymphoma (e.g. diffuse large B-cell lymphoma, mantle cell lymphoma), T-cell leukaemia/lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, or Burkett's lymphoma; a hematopoietic tumour of myeloid lineage, for example leukemias, acute and chronic myelogenous leukemias, chronic myelomonocytic leukemia (CMML), myeloproliferative disorder, myeloproliferative syndrome, myelodysplastic syndrome, or promyelocytic leukemia; multiple myeloma; thyroid follicular cancer; hepatocellular cancer, a tumour of mesenchymal origin (e.g. Ewing's sarcoma), for example fibrosarcoma or rhabdomyosarcoma; a tumour of the central or peripheral nervous system, for example astrocytoma, neuroblastoma, glioma (such as glioblastoma multiforme) or schwannoma; melanoma; seminoma; teratocarcinoma; osteosarcoma; xeroderma pigmentosum; keratoctanthoma; thyroid follicular cancer; or Kaposi's sarcoma.

Particular examples of cancers which may be treated (or inhibited) include B-cell malignancies, such as multiple myeloma, hodgkins lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma or chronic lymphocytic leukemia, with mutations in the non-canonical NFkB signalling pathway (eg in NIK (MAP3K14), TRAF3, TRAF2, BIRC2 or BIRC3 genes).

Hence, the invention relates to compounds of Formula (I), the tautomers and the stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvates thereof, for use as a medicament.

The invention also relates to the use of a compound of Formula (I), a tautomer or a stereoisomeric form thereof, or a pharmaceutically acceptable addition salt, or a solvate thereof, or a pharmaceutical composition according to the invention, for the manufacture of a medicament.

The present invention also relates to a compound of Formula (I), a tautomer or a stereoisomeric form thereof, or a pharmaceutically acceptable addition salt, or a solvate thereof, or a pharmaceutical composition according to the invention, for use in the treatment, prevention, amelioration, control or reduction of the risk of disorders associated with NF-κB-inducing kinase dysfunction in a mammal, including a human, the treatment or prevention of which is affected or facilitated by inhibition of NF-κB-inducing kinase.

Also, the present invention relates to the use of a compound of Formula (I), a tautomer or a stereoisomeric form thereof, or a pharmaceutically acceptable addition salt, or a solvate thereof, or a pharmaceutical composition according to the invention, for the manufacture of a medicament for treating, preventing, ameliorating, controlling or reducing the risk of disorders associated with NF-κB-inducing kinase dysfunction in a mammal, including a human, the treatment or prevention of which is affected or facilitated by inhibition of NF-κB-inducing kinase.

The invention also relates to a compound of Formula (I), a tautomer or a stereoisomeric form thereof, or a pharmaceutically acceptable addition salt, or a solvate thereof, for use in the treatment or prevention of any one of the diseases mentioned hereinbefore.

The invention also relates to a compound of Formula (I), a tautomer or a stereoisomeric form thereof, or a pharmaceutically acceptable addition salt, or a solvate thereof, for use in treating or preventing any one of the diseases mentioned hereinbefore.

The invention also relates to the use of a compound of Formula (I), a tautomer or a stereoisomeric form thereof, or a pharmaceutically acceptable addition salt, or a solvate thereof, for the manufacture of a medicament for the treatment or prevention of any one of the disease conditions mentioned hereinbefore.

The compounds of the present invention can be administered to mammals, preferably humans, for the treatment or prevention of any one of the diseases mentioned hereinbefore.

In view of the utility of the compounds of Formula (I), a tautomer or a stereoisomeric form thereof, or a pharmaceutically acceptable addition salt, or a solvate thereof, there is provided a method of treating warm-blooded animals, including humans, suffering from any one of the diseases mentioned hereinbefore.

Said method comprises the administration, i.e. the systemic or topical administration, preferably oral administration, of a therapeutically effective amount of a compound of Formula (I), a tautomer or a stereoisomeric form thereof, or a pharmaceutically acceptable addition salt, or a solvate thereof, to warm-blooded animals, including humans.

Therefore, the invention also relates to a method for the treatment of any one of the diseases mentioned hereinbefore comprising administering a therapeutically effective amount of compound according to the invention to a patient in need thereof.

One skilled in the art will recognize that a therapeutically effective amount of the compounds of the present invention is the amount sufficient to have therapeutic activity and that this amount varies inter alias, depending on the type of disease, the concentration of the compound in the therapeutic formulation, and the condition of the patient. Generally, the amount of a compound of the present invention to be administered as a therapeutic agent for treating the disorders referred to herein will be determined on a case by case by an attending physician.

Those of skill in the treatment of such diseases could determine the effective therapeutic daily amount from the test results presented hereinafter. An effective therapeutic daily amount would be from about 0.005 mg/kg to 50 mg/kg, in particular 0.01 mg/kg to 50 mg/kg body weight, more in particular from 0.01 mg/kg to 25 mg/kg body weight, preferably from about 0.01 mg/kg to about 15 mg/kg, more preferably from about 0.01 mg/kg to about 10 mg/kg, even more preferably from about 0.01 mg/kg to about 1 mg/kg, most preferably from about 0.05 mg/kg to about 1 mg/kg body weight. A particular effective therapeutic daily amount might be from about 10 mg/kg body weight to 40 mg/kg body weight. A particular effective therapeutic daily amount might be 1 mg/kg body weight, 2 mg/kg body weight, 4 mg/kg body weight, or 8 mg/kg body weight. The amount of a compound according to the present invention, also referred to here as the active ingredient, which is required to achieve a therapeutically effect may vary on case-by-case basis, for example with the particular compound, the route of administration, the age and condition of the recipient, and the particular disorder or disease being treated. A method of treatment may also include administering the active ingredient on a regimen of between one and four intakes per day. In these methods of treatment the compounds according to the invention are preferably formulated prior to administration. As described herein below, suitable pharmaceutical formulations are prepared by known procedures using well known and readily available ingredients.

The present invention also provides compositions for preventing or treating the disorders referred to herein. Said compositions comprising a therapeutically effective amount of a compound of Formula (I), a tautomer or a stereoisomeric form thereof, or a pharmaceutically acceptable addition salt, or a solvate thereof, and a pharmaceutically acceptable carrier or diluent.

While it is possible for the active ingredient to be administered alone, it is preferable to present it as a pharmaceutical composition. Accordingly, the present invention further provides a pharmaceutical composition comprising a compound according to the present invention, together with a pharmaceutically acceptable carrier or diluent. The carrier or diluent must be “acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof.

The pharmaceutical compositions of this invention may be prepared by any methods well known in the art of pharmacy, for example, using methods such as those described in Gennaro et al. Remington's Pharmaceutical Sciences (18^(th) ed., Mack Publishing Company, 1990, see especially Part 8: Pharmaceutical preparations and their Manufacture). A therapeutically effective amount of the particular compound, in base form or addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for systemic administration such as oral, percutaneous or parenteral administration; or topical administration such as via inhalation, a nose spray, eye drops or via a cream, gel, shampoo or the like. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions: or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wettable agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause any significant deleterious effects on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on or as an ointment.

It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.

The present compounds can be used for systemic administration such as oral, percutaneous or parenteral administration; or topical administration such as via inhalation, a nose spray, eye drops or via a cream, gel, shampoo or the like. The compounds are preferably orally administered. The exact dosage and frequency of administration depends on the particular compound of Formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, extent of disorder and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention.

The compounds of the present invention may be administered alone or in combination with one or more additional therapeutic agents. Combination therapy includes administration of a single pharmaceutical dosage formulation which contains a compound according to the present invention and one or more additional therapeutic agents, as well as administration of the compound according to the present invention and each additional therapeutic agent in its own separate pharmaceutical dosage formulation. For example, a compound according to the present invention and a therapeutic agent may be administered to the patient together in a single oral dosage composition such as a tablet or capsule, or each agent may be administered in separate oral dosage formulations.

Therefore, an embodiment of the present invention relates to a product containing as first active ingredient a compound according to the invention and as further active ingredient one or more medicinal agent, more particularly, with one or more anticancer agent or adjuvant, as a combined preparation for simultaneous, separate or sequential use in the treatment of patients suffering from cancer.

Accordingly, for the treatment of the conditions mentioned hereinbefore, the compounds of the invention may be advantageously employed in combination with one or more other medicinal agents (also referred to as therapeutic agents), more particularly, with other anti-cancer agents or adjuvants in cancer therapy. Examples of anti-cancer agents or adjuvants (supporting agents in the therapy) include but are not limited to:

-   -   platinum coordination compounds for example cisplatin optionally         combined with amifostine, carboplatin or oxaliplatin;     -   taxane compounds for example paclitaxel, paclitaxel protein         bound particles (Abraxane™) or docetaxel;     -   topoisomerase I inhibitors such as camptothecin compounds for         example irinotecan, SN-38, topotecan, topotecan hcl;     -   topoisomerase II inhibitors such as anti-tumour         epipodophyllotoxins or podophyllotoxin derivatives for example         etoposide, etoposide phosphate or teniposide;     -   anti-tumour vinca alkaloids for example vinblastine, vincristine         or vinorelbine;     -   anti-tumour nucleoside derivatives for example 5-fluorouracil,         leucovorin, gemcitabine, gemcitabine hcl, capecitabine,         cladribine, fludarabine, nelarabine;     -   alkylating agents such as nitrogen mustard or nitrosourea for         example cyclophosphamide, chlorambucil, carmustine, thiotepa,         mephalan (melphalan), lomustine, altretamine, busulfan,         dacarbazine, estramustine, ifosfamide optionally in combination         with mesna, pipobroman, procarbazine, streptozocin,         temozolomide, uracil;     -   anti-tumour anthracycline derivatives for example daunorubicin,         doxorubicin optionally in combination with dexrazoxane, doxil,         idarubicin, mitoxantrone, epirubicin, epirubicin hcl,         valrubicin;     -   molecules that target the IGF-1 receptor for example         picropodophilin;     -   tetracarcin derivatives for example tetrocarcin A;     -   glucocorticoiden for example prednisone;     -   antibodies for example trastuzumab (HER2 antibody), rituximab         (CD20 antibody), gemtuzumab, gemtuzumab ozogamicin, cetuximab,         pertuzumab, bevacizumab, alemtuzumab, eculizumab, ibritumomab         tiuxetan, nofetumomab, panitumumab, tositumomab, CNTO 328;     -   estrogen receptor antagonists or selective estrogen receptor         modulators or inhibitors of estrogen synthesis for example         tamoxifen, fulvestrant, toremifene, droloxifene, faslodex,         raloxifene or letrozole;     -   aromatase inhibitors such as exemestane, anastrozole, letrazole,         testolactone and vorozole;     -   differentiating agents such as retinoids, vitamin D or retinoic         acid and retinoic acid metabolism blocking agents (RAMBA) for         example accutane;     -   DNA methyl transferase inhibitors for example azacytidine or         decitabine;     -   antifolates for example premetrexed disodium;     -   antibiotics for example antinomycin D, bleomycin, mitomycin C,         dactinomycin, carminomycin, daunomycin, levamisole, plicamycin,         mithramycin;     -   antimetabolites for example clofarabine, aminopterin, cytosine         arabinoside or methotrexate, azacytidine, cytarabine,         floxuridine, pentostatin, thioguanine;     -   apoptosis inducing agents and antiangiogenic agents such as         Bcl-2 inhibitors for example YC 137, BH 312, ABT 737, gossypol,         HA 14-1, TW 37 or decanoic acid;     -   tubuline-binding agents for example combrestatin, colchicines or         nocodazole;     -   kinase inhibitors (e.g. EGFR (epithelial growth factor receptor)         inhibitors, MTKI (multi target kinase inhibitors), mTOR         inhibitors) for example flavoperidol, imatinib mesylate,         erlotinib, gefitinib, dasatinib, lapatinib, lapatinib         ditosylate, sorafenib, sunitinib, sunitinib maleate,         temsirolimus;     -   famesyltransferase inhibitors for example tipifarnib;     -   histone deacetylase (HDAC) inhibitors for example sodium         butyrate, suberoylanilide hydroxamic acid (SAHA), depsipeptide         (FR 901228), NVP-LAQ824, R306465, quisinostat, trichostatin A,         vorinostat;     -   Inhibitors of the ubiquitin-proteasome pathway for example         PS-341, Velcade (MLN-341) or bortezomib;     -   Yondelis;     -   Telomerase inhibitors for example telomestatin;     -   Matrix metalloproteinase inhibitors for example batimastat,         marimastat, prinostat or metastat;     -   Recombinant interleukins for example aldesleukin, denileukin         diftitox, interferon alfa 2a, interferon alfa 2b, peginterferon         alfa 2b;     -   MAPK inhibitors;     -   Retinoids for example alitretinoin, bexarotene, tretinoin;     -   Arsenic trioxide;     -   Asparaginase;     -   Steroids for example dromostanolone propionate, megestrol         acetate, nandrolone (decanoate, phenpropionate), dexamethasone;     -   Gonadotropin releasing hormone agonists or antagonists for         example abarelix, goserelin acetate, histrelin acetate,         leuprolide acetate;     -   Thalidomide, lenalidomide;     -   Mercaptopurine, mitotane, pamidronate, pegademase, pegaspargase,         rasburicase;     -   BH3 mimetics for example ABT-199;     -   MEK inhibitors for example PD98059, AZD6244, CI-1040;     -   colony-stimulating factor analogs for example filgrastim,         pegfilgrastim, sargramostim; erythropoietin or analogues thereof         (e.g. darbepoetin alfa); interleukin 11; oprelvekin;         zoledronate, zoledronic acid; fentanyl; bisphosphonate;         palifermin;     -   a steroidal cytochrome P450 17alpha-hydroxylase-17,20-lyase         inhibitor (CYP17), e.g. abiraterone, abiraterone acetate.

The one or more other medicinal agents and the compound according to the present invention may be administered simultaneously (e.g. in separate or unitary compositions) or sequentially in either order. In the latter case, the two or more compounds will be administered within a period and in an amount and manner that is sufficient to ensure that an advantageous or synergistic effect is achieved. It will be appreciated that the preferred method and order of administration and the respective dosage amounts and regimes for each component of the combination will depend on the particular other medicinal agent and compound of the present invention being administered, their route of administration, the particular tumour being treated and the particular host being treated. The optimum method and order of administration and the dosage amounts and regime can be readily determined by those skilled in the art using conventional methods and in view of the information set out herein.

The weight ratio of the compound according to the present invention and the one or more other anticancer agent(s) when given as a combination may be determined by the person skilled in the art. Said ratio and the exact dosage and frequency of administration depends on the particular compound according to the invention and the other anticancer agent(s) used, the particular condition being treated, the severity of the condition being treated, the age, weight, gender, diet, time of administration and general physical condition of the particular patient, the mode of administration as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that the effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention. A particular weight ratio for the present compound of Formula (I) and another anticancer agent may range from 1/10 to 10/1, more in particular from 1/5 to 5/1, even more in particular from 1/3 to 3/1.

The platinum coordination compound is advantageously administered in a dosage of 1 to 500 mg per square meter (mg/m2) of body surface area, for example 50 to 400 mg/m2, particularly for cisplatin in a dosage of about 75 mg/m2 and for carboplatin in about 300 mg/m2 per course of treatment.

The taxane compound is advantageously administered in a dosage of 50 to 400 mg per square meter (mg/m2) of body surface area, for example 75 to 250 mg/m2, particularly for paclitaxel in a dosage of about 175 to 250 mg/m2 and for docetaxel in about 75 to 150 mg/m2 per course of treatment.

The camptothecin compound is advantageously administered in a dosage of 0.1 to 400 mg per square meter (mg/m2) of body surface area, for example 1 to 300 mg/m2, particularly for irinotecan in a dosage of about 100 to 350 mg/m2 and for topotecan in about 1 to 2 mg/m2 per course of treatment.

The anti-tumour podophyllotoxin derivative is advantageously administered in a dosage of 30 to 300 mg per square meter (mg/m2) of body surface area, for example 50 to 250 mg/m2, particularly for etoposide in a dosage of about 35 to 100 mg/m2 and for teniposide in about 50 to 250 mg/m2 per course of treatment.

The anti-tumour vinca alkaloid is advantageously administered in a dosage of 2 to 30 mg per square meter (mg/m2) of body surface area, particularly for vinblastine in a dosage of about 3 to 12 mg/m2, for vincristine in a dosage of about 1 to 2 mg/m2, and for vinorelbine in dosage of about 10 to 30 mg/m2 per course of treatment.

The anti-tumour nucleoside derivative is advantageously administered in a dosage of 200 to 2500 mg per square meter (mg/m2) of body surface area, for example 700 to 1500 mg/m2, particularly for 5-FU in a dosage of 200 to 500 mg/m2, for gemcitabine in a dosage of about 800 to 1200 mg/m2 and for capecitabine in about 1000 to 2500 mg/m2 per course of treatment.

The alkylating agents such as nitrogen mustard or nitrosourea is advantageously administered in a dosage of 100 to 500 mg per square meter (mg/m2) of body surface area, for example 120 to 200 mg/m2, particularly for cyclophosphamide in a dosage of about 100 to 500 mg/m2, for chlorambucil in a dosage of about 0.1 to 0.2 mg/kg, for carmustine in a dosage of about 150 to 200 mg/m2, and for lomustine in a dosage of about 100 to 150 mg/m2 per course of treatment.

The anti-tumour anthracycline derivative is advantageously administered in a dosage of 10 to 75 mg per square meter (mg/m2) of body surface area, for example 15 to 60 mg/m2, particularly for doxorubicin in a dosage of about 40 to 75 mg/m2, for daunorubicin in a dosage of about 25 to 45 mg/m2, and for idarubicin in a dosage of about 10 to 15 mg/m2 per course of treatment.

The antiestrogen agent is advantageously administered in a dosage of about 1 to 100 mg daily depending on the particular agent and the condition being treated. Tamoxifen is advantageously administered orally in a dosage of 5 to 50 mg, preferably 10 to 20 mg twice a day, continuing the therapy for sufficient time to achieve and maintain a therapeutic effect. Toremifene is advantageously administered orally in a dosage of about 60 mg once a day, continuing the therapy for sufficient time to achieve and maintain a therapeutic effect. Anastrozole is advantageously administered orally in a dosage of about 1 mg once a day. Droloxifene is advantageously administered orally in a dosage of about 20-100 mg once a day. Raloxifene is advantageously administered orally in a dosage of about 60 mg once a day. Exemestane is advantageously administered orally in a dosage of about 25 mg once a day.

Antibodies are advantageously administered in a dosage of about 1 to 5 mg per square meter (mg/m2) of body surface area, or as known in the art, if different. Trastuzumab is advantageously administered in a dosage of 1 to 5 mg per square meter (mg/m2) of body surface area, particularly 2 to 4 mg/m2 per course of treatment.

These dosages may be administered for example once, twice or more per course of treatment, which may be repeated for example every 7, 14, 21 or 28 days.

The following examples further illustrate the present invention.

EXAMPLES

Several methods for preparing the compounds of this invention are illustrated in the following examples. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. Hereinafter, the term ‘ACN’ or ‘MeCN’ means acetonitrile, ‘AcOH’ means acetic acid, ‘Ar’ means argon, ‘BINAP’ means 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, ‘BOC’ means tert-butyloxycarbonyl, ‘ACN’ or ‘MeCN’ means acetonitrile, ‘Boc₂O’ means di-tert-butyl dicarbonate, ‘Celite®’ means diatomaceous earth, ‘CMBP’ means (cyanomethylene)tributylphosphorane, ‘DCM’ means dichloromethane, ‘DIEA’ or ‘DIPEA’ means diisopropylethylamine, ‘DiPE’ means diisopropylether, ‘DMAP’ means dimethylaminopyridine, ‘DMF’ means dimethylformamide, ‘dppf’ means [1,1′-Bis(diphenylphosphino)ferrocene], ‘Et₂O’ means diethylether, ‘EtOH’ means ethanol, ‘EtOAc’ or ‘AcOEt’ means ethyl acetate, ‘ee’ means enantiomeric excess, ‘HATU’ means 1-[bis(dimethylamino)methylene]-1H-[1,2,3]triazolo [4,5-b]pyridin-1-ium 3-oxide hexafluorophosphate, ‘HPLC’ means High-performance Liquid Chromatography, ‘iPrOH’ means isopropyl alcohol, ‘iPrNH₂’ means isopropyl amine, ‘LC/MS’ means Liquid Chromatography/Mass Spectrometry, ‘LiHMDS’ means Lithium bis(trimethylsilyl)amide, ‘Me-THF’ means 2-methyl-tetrahydrofuran, ‘MeNH₂’ means monomethylamine, ‘MeOH’ means methanol, ‘MsCl’ means methanesulfonyl chloride, ‘MTBE’ means methyl tert-butyl ether ‘NBS’ means N-bromosuccinimide, ‘NCS’ means N-chlorosuccinimide, ‘NMR’ means Nuclear Magnetic Resonance, ‘o/n’ means overnight, ‘OR’ means optical rotation, ‘Pd/C 10%’ means palladium on carbon loading 10%, ‘Pd-118’ means dichloro [1,1′-bis(di-tert-butylphosphino)ferrocene] palladium(II), ‘PdCl₂(dppf).DCM’ means [1,1′-Bis(diphenylphosphino)ferrocene] dichloropalladium(II) complex with DCM, ‘Pd(OAc)₂’ means palladium (II) acetate, ‘Pd(PPh₃)₄’ means tetrakis(triphenylphosphine)palladium (0), ‘Pd(t-Bu₃P)₂’ means bis(tri-tert-butyl-phosphine) palladium (0), ‘PdCl₂dppf’ or ‘Pd(dppf)Cl₂’ means [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), ‘Pd(OH)₂/C’ means palladium hydroxide on carbon, ‘Psi’ means Pounds per Square Inch (pressure), ‘Pybrop’ means bromotripyrrolidinophosphonium hexafluorophosphate, ‘rt’ means room temperature, ‘SFC’ means supercritical fluid chromatography, ‘T’ means temperature, ‘TBAF’ means tetrabutylammonium fluoride, ‘TBDMS’ or ‘SMDBT’ means tert-butyldimethylsilyl, ‘TEA’ or ‘Et₃N’ means triethylamine, ‘TFA’ means trifluoroacetic acid, ‘THF’ means tetrahydrofuran, CV′ means column volumes, ‘Quant.’ means quantitative, ‘min’ or ‘mn’ means minute(s), ‘W’ means microwave, ‘equiv.’ means equivalent(s), ‘M.P.’ or ‘m.p.’ means melting point, ‘v/v’ means volume/volume %.

When a stereocenter is indicated with ‘RS’ this means that a racemic mixture was obtained.

It is well known to one skilled in the art that protecting groups such as TBDMS can routinely be removed with TBAF in a variety of solvents such as for example THF.

Similarly, conditions for removal of BOC protecting groups are well known to one skilled in the art, commonly including for example TFA in a solvent such as for example DCM, or HCl in a solvent such as for example dioxane.

The skilled person will realize that in some cases where an organic layer was obtained at the end of an experimental protocol, it was necessary to dry the organic layer with a typical drying agent such as for example MgSO₄, or by azeotropic distillation, and to evaporate the solvent before using the product as a starting material in the next reaction step.

A. Preparation of the Intermediates Example A1 Preparation of Intermediate 1

To a solution of 2,4-dibromo-6-cyanoaniline (200.00 g, 724.82 mmol) and DMAP (17.71 g, 144.96 mmol) in DCM (3 L), Boc₂O (474.58 g, 2.17 mol) was added and the reaction mixture was stirred at 45° C. for 4 h. The crude mixture was successively washed with saturated NaHCO₃ (2×1 L) and brine (2×1 L), dried over MgSO₄, filtered and concentrated under vacuum to give 323 g of intermediate 1 (56% yield, yellow solid, 86% purity evaluated by LC/MS). The product was used in the next step without any further purification.

Preparation of Intermediate 2

A mixture of intermediate 1 (620.00 g, 1.30 mol) and K₂CO₃ (539.02 g, 3.90 mol) in MeOH (6 L) was stirred at 65° C. for 3 h. The reaction mixture was cooled to 25° C. filtered and concentrated under vacuum. Then, the residue was dissolved in EtOAc (4 L) and the organic layer was washed with brine (2 L), dried over MgSO₄, and filtered. The filtrate was evaporated under vacuum to 1/8 solvent, filtered to collect the solid and dried under reduced pressure to give 300 g of intermediate 2 (60% yield, yellow solid). The product was used in the next step without any further purification.

Preparation of Intermediate 3

Intermediate 2 (100.00 g, 265.93 mmol), 2-(((tert-butyl-dimethyl-silanyl)oxy) methyl) prop-2-en-1-ol (80.72 g, 398.90 mmol) and tributylphosphane (107.61 g, 531.86 mmol) were dissolved in THF (2 L) and cooled to 0° C. A solution of 1,1′-(azodicarbonyl)-dipiperidine (147.61 g, 585.05 mmol) in THF (50 mL) was added dropwise under N₂ and stirred at 0° C. for 1 h, then 25° C. for 12 h. The resulting mixture was triturated with petroleum ether (3 L), filtered and concentrated under vacuum. Then, the residue was dissolved in EtOAc (6 L), washed successively with water (2×2 L) and brine (2×2 L), dried over MgSO₄, filtered and concentrated under vacuum. Three reactions (each 100 g) were carried out in parallel. The resulting residues were purified by column chromatography on silica gel (SiO₂, mobile phase: petroleum ether/EtOAc, 10:1). The desired fractions were collected and the solvent was concentrated to dryness under vacuum to give 350 g of intermediate 3 (78% yield, yellow oil).

Preparation of Intermediate 3a

Triethylamine (196.3 mL; 1.408 mol) was added to a solution of 2-(((tert-butyl-dimethyl-silanyl)oxy) methyl) prop-2-en-1-ol (114 g, 563.3 mmol) in DCM (1 L) at 0° C. Methanesulfonylchloride (56.0 mL; 704.2 mmol) was slowly added to the mixture and this mixture was stirred for 2 h at 0° C. The reaction was quenched with saturated aqueous solution of NaHCO₃ (100 ml) and extracted with DCM (500 ml*2). The organic layer was dried over MgSO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (Petroleum ether/ethyl acetate from 0/100 to 5/1) to give 50 g (32%; light yellow oil) of intermediate 3a.

Alternative Preparation of Intermediate 3

Intermediate 2 (140 g; 372.3 mmol) was dissolved in acetonitrile (1.3 L). Intermediate 3a (104.4 g; 372.3 mmol), potassium carbonate (128.6 g; 930.7 mmol sodium iodide (5.58 g; 37.2 mmol) were added. The mixture was stirred at 80° C. for 12 h, cooled and concentrated under reduced pressure. The residue was dissolved in water (1 L) and extracted with ethyl acetate (1 L*2).

The combined organic phase was washed with brine (1 L), dried over Na₂SO₄ and filtered. The filtrate was concentrated under vacuum to give a crude product. The residue was purified by silica gel chromatography (Petroleum ether/ethyl acetate from 100/0 to 40/1) to give 180 g (86%; clear oil) of intermediate 3.

Preparation of Intermediate 4 and Intermediate 4′

A suspension of intermediate 3 (120.00 g, 214.14 mmol), sodium acetate (45.67 g, 556.76 mmol), sodium formate (37.86 g, 556.76 mmol), Pd(OAc)₂ (4.81 g, 21.41 mmol) and tetraethylammonium chloride (44.35 g, 267.67 mmol) in DMF (1.26 L) was degassed under vacuum, purged with Ar three times, and stirred at 85° C. for 2 h. The resulting mixture was filtered through a pad of Celite® and the solid was washed with DCM (2 L). The filtrate was concentrated under vacuum. The residue was dissolved in ethyl acetate (4 L), washed successively with water (2×2 L) and brine (2×2 L), dried over MgSO₄, filtered and concentrated under vacuum. Then, the residue was purified by column chromatography on silica gel (SiO₂, mobile phase: petroleum ether/EtOAc, 15:1). The desired fractions were collected and the solvent was concentrated to dryness under vacuum to give a mixture of intermediates 5 and 5′. Three reactions (each on 100-120 g of intermediate 3) were carried out in parallel which gave in total 160 g of a mixture of intermediates 4 and 4′ (38:62).

Alternative Preparation of Intermediate 4

To a mixture of intermediates 4 and 4′ in CH₃CN (1.60 L), 1-bromopyrrolidine-2,5-dione (212.20 g, 1.19 mol) was added and stirred at 40° C. for 16 h. The solvent was removed by evaporation under reduced pressure. The residue was dissolved in ethyl acetate (2 L), washed successively with NaHCO₃ (2×1 L) and brine (2×1 L), dried over MgSO₄ and filtered. The filtrate was evaporated under vacuum and purified by column chromatography on silica gel (SiO₂, mobile phase: petroleum ether/EtOAc, 50:1). The desired fractions were collected and the solvent was concentrated to dryness under vacuum to give 110.00 g of intermediate 4 (56% yield, yellow oil, 97% purity evaluated by LC/MS).

Alternative Preparation of Intermediate 4R

To a solution of intermediate 4′R (10.0 g) in ACN (100 mL) 1,3-dibromo-5,5-dimethylhydantoin (0.75 eq.) was added and the mixture was stirred at 20° C. for 24-28 hours, monitoring the conversion by HPLC. After complete conversion aqueous 5% NaHCO₃ was added (250 mL) and the mixture was stirred for 30 minutes. Toluene (250 mL) was then added and, after 30 min stirring at room temperature, the mixture was allowed to settle and the layers were separated. The organic layer was washed twice with water (100 mL) and used directly in the next reaction step (conversion 99.6%).

Alternative Preparation a of Intermediate 4′

To a solution of intermediate 3 (295.00 g, 473.70 mmol), sodium acetate (101.05 g, 1.23 mol), sodium formate dihydrate (128.15 g, 1.23 mol) and [1,1′-bis(diphenylphosphino) ferrocene] palladium, (II) chloride complex with dichloromethane (19.34 g, 23.70 mmol) in DMF (2 L), tetra-N-butylammonium chloride (164.60 g, 592.20 mmol) was added under N₂ at rt. The reaction mixture was stirred overnight at 60° C., then, filtered through a pad of Celite® and the solid was washed with DCM (400 mL). The filtrate was concentrated under vacuum. The resulting residue was dissolved in EtOAc (4 L) and the organic layer was washed successively with water (2 L) and brine (2 L), dried over Na₂SO₄, filtered and concentrated to give the crude product as black oil. This residue was purified by column chromatography on silica gel (SiO₂, mobile phase: petroleum ether/EtOAc, gradient from 100:0 to 10:1). The desired fractions were collected and the solvent was concentrated to dryness under vacuum to give 155 g of intermediate 4′ (70% yield, yellow oil).

Alternative Preparation B of Intermediate 4′

Intermediate 583 (50.0 g) was dissolved in DMF (250 mL). Sodium formate dehydrate (2.6 eq.), sodium acetate (2.6 eq.), tetraethylammonium chloride (1.25 eq.) and palladium acetate (0.05 eq.) were added. The mixture was degassed with nitrogen (3 times) and was then warmed at 45-50° C. until complete conversion (approximately 24 hours monitored by HPLC). Water (350 mL) was then added followed by heptane (350 mL). The mixture was filtered and, after phase separation, the aqueous layer was extracted with heptane (350 mL). The combined organic layers were washed with water (250 mL) and then filtered on a diatomite pad (25 g; diatomaceous earth). The filtrate was concentrated to 100-150 mL, cooled to −10 to −5° C. for 2 hours and filtered to afford 37.6 g of intermediate 4′. An additional amount of intermediate 4′ could be recovered by filtering the mother liquors on a silica gel pad to remove impurities, and subsequently cool down the filtrate to −10° C. to crystallize out an additional amount of intermediate 4′.

Preparation of Intermediate 4′R Intermediate 4′R

Intermediate 4′R was obtained from a chiral chromatography separation of intermediate 4′ (column CHIRALPAK IC 5 cm*25 cm; mobile phase: hexane/EtOH:80/20; Flow rate: 60.0 mL/min; Wavelenght: UV 254 nm; Temperature: 35° C.).

Preparation of Intermediate 4R and Intermediate 4S

Intermediate 4 (500 g) was purified via Normal Phase Chiral separation (Stationary phase: Daicel Chiralpak IC 2000 gram 10 microhm, mobile phase: heptane/EtOH, Isocratic 80% heptane, 20% EtOH). The fractions containing the products were mixed and concentrated to afford 266 g of intermediate 4R (53% yield, ee>98%) and 225 g of intermediate 4S (45% yield, ee>98%).

Alternatively, intermediate 4 (10 g) was purified by chiral SFC (Stationary phase: CHIRALPAK IC 5 μm 250×30 mm, mobile phase: 85% CO₂, 15% iPrOH). The pure fractions were collected and evaporated to dryness yielding 4.3 g of intermediate 4R (43% yield, ee=100%) and 4.5 g of intermediate 4S (45% yield, ee=100%).

Example A2

Preparation of Intermediate 5

To a solution of intermediate 4 (127.00 g, 234.70 mmol) in 1,4-dioxane (1.2 L), bis(pinacolato)diboron (74.50 g, 293.40 mmol) and potassium acetate (69.11 g, 704.24 mmol) were added. Then, [1,1′-bis(diphenylphosphino) ferrocene] palladium, (II) chloride (8.59 g, 11.74 mmol) was added and stirred for 4 h at 85° C. under N₂ atmosphere. The mixture was cooled, partitioned between EtOAc (2 L) and water (500 mL) and filtered through a pad of Celite®. The organic and aqueous layers were separated. The organic layer was washed successively with water (300 mL), brine (300 mL), dried over Na₂SO₄ and concentrated under vacuum. The residue was dissolved in a mixture of DCM/EtOAc (90:10, 600 mL), filtered through a plug of flash silica gel, washed with DCM/EtOAc (90:10, 3 L). The filtrate was evaporated to give 125 g of crude intermediate 5 (brown oil) which was directly engaged in the next step.

Preparation of Intermediate 5R

To a solution of intermediate 4R (20.00 g, 41.50 mmol) in 1,4-dioxane (200 mL), bis(pinacolato)diboron (13.20 g, 51.90 mmol) and potassium acetate (12.20 g, 124.60 mmol) were added. Then, [1,1′-bis(diphenylphosphino) ferrocene] palladium, (II) chloride complex with dichloromethane (1.70 g, 2.08 mmol) was added and stirred for 4 h at 85° C. under N₂. The mixture was cooled, partitioned between EtOAc (200 mL) and water (100 mL), and filtered through a pad of Celite®. The organic and aqueous layers were separated. The organic layer was washed successively with water (100 mL), brine (100 mL), dried over Na₂SO₄, and concentrated under vacuum. The residue was dissolved in a mixture of DCM/EtOAc (90:10, 200 mL), filtered through a plug of flash silica gel and washed with a mixture of DCM/EtOAc (90:10, 1 L). The filtrate was evaporated to give 25 g of crude intermediate 5R (brown oil) which was directly engaged in the next step.

Preparation of Intermediate 6

A solution of intermediate 5 (160.00 g, 302.70 mmol) in 1,4-dioxane (1.2 L) was treated with a solution of NaHCO₃ (76.30 g, 908.10 mmol) in water (400 mL). Then, 2,4-dichloropyrimidine (67.64 g, 545.06 mmol) and Pd(PPh₃)₄ (17.50 g, 15.13 mmol) were added under N₂. The reaction mixture was stirred at 80° C. under N₂. The mixture was cooled, partitioned between EtOAc (2 L) and water (800 mL), and the mixture was filtered through a pad of Celite®. The organic and aqueous layers were separated. The organic layer was washed successively with water (800 mL) and brine (500 mL), dried over Na₂SO₄ and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (SiO₂, mobile phase: petroleum ether/EtOAc, gradient from 100:0 to 10:1). The desired fractions were collected and the solvent was concentrated to dryness under vacuum to give 100 g of intermediate 6 (71% yield in 2 steps, yellow solid).

Preparation of Intermediate 6R and intermediate 6S

Intermediate 6 (52.00 g) was purified by chiral SFC (stationary phase: CHIRALPAK IC 5 μm 250×30 mm, mobile phase: 60% CO₂, 40% MeOH). The desired fractions were collected and the solvent was concentrated to dryness under vacuum to give 25 g of intermediate 6R (48% yield) and 25.1 g of intermediate 6S (48% yield).

Intermediate 6R (50.10 g) was further purified by chiral SFC (stationary phase: CHIRALPAK IA 5 μm 250*20 mm, mobile phase: 87.5% CO₂, 12.5% MeOH). The pure fractions were mixed and the solvent was evaporated to afford 49.10 g of intermediate 6R.

Alternative Preparation A of Intermediate 6R

A solution of intermediate 5R (25.00 g, 41.90 mmol) in 1,4-dioxane (1.2 L) was treated with a solution of NaHCO₃ (10.50 g, 125.72 mmol) in water (80 mL). Then, 2,4-dichloropyrimidine (9.36 g, 62.86 mmol) and Pd(PPh₃)₄ (2.42 g, 2.09 mmol) were added under N₂. The reaction mixture was stirred at 80° C. under N₂. The mixture was cooled, partitioned between EtOAc (300 mL) and water (100 mL), and filtered through a pad of Celite®. The organic layer was washed with water (100 mL), brine (100 mL), dried over Na₂SO₄ and concentrated under vacuum. The resulting residue was combined with 3 other batches coming from reactions performed on 25 g of intermediate 5R. The residue was purified by flash column chromatography on silica gel (SiO₂, mobile phase: petroleum ether/EtOAc, gradient from 100:0 to 10:1). The desired fractions were collected and the solvent was concentrated to dryness under vacuum to give 63 g of intermediate 6R (70% yield over 2 steps, yellow solid).

Alternative Preparation B of Intermediate 6R

To a solution of intermediate 4R (50.0 g) in toluene (400 mL) was added bis(pinacolato)diboron (1.3 eq.), potassium acetate (3.0 eq.) and Pd(dppf)Cl₂ (0.05 eq.). The mixture was degassed 3 times with nitrogen and heated to 90° C. for 12-14 hours. Subsequently, the mixture was cooled to room temperature and filtered on a celite pad which was washed with toluene (150 mL). The filtrate was washed with water (250 mL) and was then filtered on a silica pad (10 g) to afford a toluene solution containing 49 g of intermediate 5R. To this solution was added 2,4-dichloropyrimidine (1.5 eq.), NaHCO₃ (3.0 eq.), water (25 mL) and Pd(PPh₃)₄ (0.05 eq.). After degassing three times with nitrogen, the mixture was stirred at 90° C. monitoring the conversion by HPLC. After complete conversion (24-48 hours), the mixture was cooled to room temperature, filtered on a celite pad and washed with water (250 mL). To the organic layer was added silica thiol scavenging resin (10 g; resin used to scavenge metals) and the mixture was stirred at 90° C. for 3 hours, then cooled to room temperature and filtered. The solvent was switched completely to isopropanol by repeated distillation until about 100 mL of isopropanol solution remained. The solution was warmed to 50° C. and 250 mL of methanol were added. After stirring at 50° C. for 4 hours, the mixture was cooled to 0° C. in 4 h, held at the same temperature for 16 hours and finally filtered to obtain 26 g of intermediate 6R.

The intermediate in the Table below was prepared by using an analogous method to that described as the alternative method A for intermediate 6R, starting from the respective starting materials indicated. The most relevant minor deviations to the referenced method are indicated as additional information in the column ‘Yield (%)’.

Intermediate number Structure Mass (mg) Yield (%) Intermediate 104i

320 LCMS 88% 28 Procedure with PdCl₂(dppf).DCM, 80° C., o.n

Example A3 Preparation of Intermediate 7R

In a three neck round bottom flask, SiO₂ (35-70 μm) (200 g) was added to a solution of intermediate 6R (45.00 g, 87.36 mmol) in toluene (640 mL) at rt. The reaction mixture was reflux (bath temperature 125° C.) for 6 h under mechanical agitation. Then, SiO₂ (35-70 μm) was filtered off, washed successively with THF and EtOAc, and the filtrate was evaporated to dryness to give 37.2 g of crude intermediate 7R which was directly engaged in the next steps.

Alternative Preparation of Intermediate 7R

TFA (135 mL, 1.76 mol) was added dropwise at −10° C. (over 50 min) to a solution of intermediate 6R (20.00 g, 38.82 mmol) in DCM (550 mL). The reaction mixture was stirred below 0° C. for 15 min more, then poured in a mixture of crushed ice and a saturated aqueous solution of K₂CO₃. After extraction with DCM (twice), the organic layers were combined, washed with an aqueous solution of K₂CO₃, dried over MgSO₄ and evaporated to dryness. The residue (17.40 g) was purified by chromatography on silica gel (irregular SiOH, 80 g, mobile phase: NH₄OH/MeOH/DCM, gradient from 0% NH₄OH, 0% MeOH, 100% DCM to 0.2% NH₄OH, 2% MeOH, 98% DCM). The desired fractions were collected and the solvent was concentrated to dryness under vacuum to give 12.1 g of intermediate 7R (75% yield).

Preparation of Intermediate 7

To a solution of intermediate 7 (1.50 g, 2.91 mmol) in DCM (30 mL), TFA (7 mL, 91.50 mmol) was added at 0-5° C. and stirred at 0-5° C. for 1 h, then rt for 1 h. The crude product was poured in a mixture of crushed ice and a saturated aqueous solution of NaHCO₃. After extraction with DCM (twice), the organic layers were combined, washed with a saturated solution of NaHCO₃, dried over MgSO₄ and concentrated under vacuum. The residue was purified by column chromatography on silica gel (Irregular SiOH, 40 μm, mobile phase: NH₄OH/MeOH/DCM, gradient from 0% NH₄OH, 0% MeOH, 100% DCM to 0.1% NH₄OH, 2% MeOH, 98% DCM). The desired fractions were collected and the solvent was concentrated to dryness under vacuum to give 524 mg of intermediate 7 (65% yield).

Example A4 Preparation of Intermediate 331

A solution of intermediate 2 (10.00 g, 26.59 mmol) and 2-methyl-2-propen-1-ol (4.50 mL, 53.69 mmol) in Me-THF (200 mL) was cooled with EtOH/ice bath under N₂ to an internal temperature of −5° C. Tri-n-butylphosphine (13.30 mL, 53.19 mmol) was added. Then a solution of 1,1′-(azodicarbonyl)piperidine (14.80 g, 58.62 mmol) in Me-THF (120 mL) was added dropwise over 25 min. The solution was stirred for 5 min more at this temperature then the cooling bath was removed and the solution stirred at rt for 18 h. The reaction mixture was poured onto a 10% aqueous solution of K₂CO₃ and extracted with DCM. The organic layer was decanted, dried over MgSO₄, filtered and evaporated to dryness. The residue (20 g) was taken up with heptane and the insoluble material was removed by filtration. The filtrate was concentrated to 20 mL and purified by column chromatography on silica gel (irregular SiOH, 80 g, mobile phase: heptane/EtOAc, gradient from 100:0 to 88:12). The pure fractions were collected and evaporated to dryness to give 10.80 g of intermediate 331 (94% yield).

Preparation of Intermediate 332 and intermediate 332′

A mixture of intermediate 331 (10.80 g, 25.11 mmol), sodium acetate (5.35 g, 65.28 mmol), sodium formate (4.44 g, 65.28 mmol) and tetraethylammonium chloride (5.20 g, 31.38 mmol) in DMF (100 mL) was de-gassed by sonication for 10 min under a stream of Ar. Pd(OAc)₂ (563.00 mg, 2.51 mmol) was added and the resulting orange suspension was then stirred at 85° C. (block temperature) for 4 h. The residue was diluted with EtOAc and water, then filtered through a plug of Celite®. The organic layer was decanted, washed successively with a saturated aqueous solution of NaHCO₃ and brine, dried over MgSO₄, filtered and evaporated to dryness. The residue (8.3 g, mixture of intermediates 332 and 332′) was dissolved in CH₃CN (230 mL) and NBS (4.47 g, 25.11 mmol) was added. The reaction mixture was heated at 55° C. (block temp) for 18 h. The reaction mixture was evaporated to dryness and the residue was taken up with heptane/DCM. The precipitate was filtered off (1 g derivative) and the filtrate (10 g) was purified by column chromatography on silica gel (irregular SiOH, 120 g, injection in DCM, mobile phase: heptane/EtOAc, gradient from 100:0 to 80:20). The pure fractions were collected and evaporated to dryness to give 4 g of intermediate 332 (45% yield).

Preparation of Intermediate 333

[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane (243.00 mg, 0.30 mmol) was added to a solution of intermediate 332 (2.09 g, 5.95 mmol), bis(pinacolato)diboron (1.90 g, 7.44 mmol) and potassium acetate (1.75 g, 17.85 mmol) in 1,4-dioxane (45 mL) and the reaction mixture was heated for 18 h at 85° C. The reaction mixture was diluted with EtOAc and filtered through a pad of Celite®. The filtrate was washed with water, and the organic layer was decanted, dried over MgSO₄, filtered and evaporated to dryness. The residue was crystallized from DiPE and the precipitate was filtered and dried to give 1.85 g of intermediate 333 (78% yield).

Preparation of Intermediate 334

A degassed suspension of intermediate 333 (1.12 g, 2.81 mmol), 2,4-dichloropyridine (502.00 mg, 3.37 mmol), Pd(PPh₃)₄ (162.00 mg, 0.14 mmol) and a solution of Na₂CO₃ 2M (4.20 mL, 8.14 mmol) in 1,4-dioxane (24 mL) was heated to 85° C. for 18 h. The reaction mixture was partitioned between DCM and saturated aqueous NaHCO₃. The organic layer was decanted, dried over MgSO₄, filtered and evaporated to dryness. The residue (2 g) was purified by column chromatography on silica gel (irregular SiOH, 40 g, mobile phase: heptane/EtOAc, gradient from 70:30 to 50:50). The pure fractions were collected and evaporated to dryness to give 933 mg of intermediate 334 (86% yield, 85% purity based on LC/MS).

Example A5 Preparation of Intermediate 343

To a solution of intermediate 5 (3.89 g, 4.92 mmol), 5-fluoro-2,4-dichloropyrimidine (1.07 g, 6.40 mmol) and Cs₂CO₃ (4.81 g, 14.80 mmol) in 1,4-dioxane (25 mL) and distilled water (2.5 mL), Pd(PPh₃)₄ (0.28 g, 0.25 mmol) was added and the reaction mixture was heated overnight at 95° C. The mixture was poured into ice and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO₄, filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (240 g, 15-40 μm, mobile phase: heptane/EtOAc, gradient from 1:0 to 0:1). The pure fractions were mixed and the solvent was evaporated to give 1.92 g of intermediate 343 (73% yield).

The intermediates in the Table below were prepared by using an analogous starting from the respective starting materials.

Intermediate number Structure Mass (mg) Yield (%) Intermediate 348

1820 83

Example A6 Preparation of Intermediate 372

Intermediate 4 (4.00 g, 8.31 mmol) was dissolved in THF (81 mL) and a TBAF solution in THF (1M, 16.60 mL, 16.60 mmol) was added. After stirring at rt for 4 h, the solvent was evaporated under vacuum. The residue was extracted with EtOAc/water and the organic phase was washed twice with water, once with brine, dried over anhydrous MgSO₄ and evaporated to dryness under vacuum to provide a yellow oil. The residue (4.5 g) was purified by column chromatography on silica gel (irregular SiOH, 80 g, mobile phase: heptane/EtOAc, gradient from 80:20 to 50:50). The fractions containing the product were combined and evaporated to provide 2.54 g of intermediate 372 (83% yield, white powder).

Preparation of Intermediate 373

A solution of intermediate 372 (2.00 g, 5.45 mmol) and ethylbromoacetate (722.80 μL, 6.53 mmol) in dry DMF (15 mL) was cooled to 0° C. After stirring for 5 min, NaH (60% dispersed in mineral oil) (261.40 mg, 6.53 mmol) was then added and the reaction mixture was stirred at 0° C. for 1 h. The reaction was poured onto a mixture of Et₂O and aqueous NaHCO₃. The organic layer was decanted, washed thrice with brine, dried over MgSO₄ and evaporated to dryness. The residue was purified by column chromatography on silica gel (irregular SiOH, 80 g, mobile phase: heptane/EtOAc, gradient from 80:20 to 50:50). The pure fractions were collected and evaporated to dryness to give 2.04 g of intermediate 373 (82% yield, 95% purity based on LC/MS).

Preparation of Intermediate 374

NaBH₄ (250.40 mg, 6.62 mmol) was added portionwise to a solution of intermediate 373 (2.00 g, 4.41 mmol) in a mixture of THF (24 mL) and MeOH (8 mL) and the reaction mixture was heated at 55° C. for 45 min. The reaction mixture was cooled to rt, poured onto water and extracted with Et₂O. The organic layer was decanted, dried over MgSO₄, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel (irregular SiOH, 40 g, mobile phase: heptane/EtOAc, gradient from 80:20 to 50:50). The pure fractions were collected and evaporated to dryness to give 810 mg of intermediate 374 (45% yield).

Preparation of Intermediate 375 and intermediate 375′

A mixture of intermediate 374 (1.50 g, 3.65 mmol), bis(pinacolato)diboron (1.15 g, 4.56 mmol) and acetic acid potassium salt (715.90 mg, 7.29 mmol) in Me-THF (30 mL) was purged with N₂. [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane (298.60 mg, 0.36 mmol) was added and the mixture was purged with N₂ and stirred for 18 h at 100° C. The reaction mixture was diluted with EtOAc, washed with water then brine, dried over MgSO₄ and evaporated to dryness to give 2.76 g of intermediate 375 in a mixture with intermediate 375′ (75:20+5% of impurities not defined) and used as it in the next step.

Preparation of Intermediate 376

A solution of intermediate 375 (1.67 g, 3.65 mmol), 2,4-dichloropyrimidine (652.00 mg, 4.38 mmol) and K₃PO₄ (1.80 g, 7.29 mmol) in a mixture of Me-THF (30 mL) and distilled water (6.5 mL) was degassed with N₂. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane (238.85 mg, 0.29 mmol) was added and the reaction mixture was heated at 85° C. for 18 h. The reaction mixture was diluted with EtOAc, washed with water then with brine, dried over MgSO₄ and evaporated to dryness. The residue (2.4 g) was purified by column chromatography on silica gel (irregular SiOH, 40 g, mobile phase: heptane/EtOAc, gradient from 50:50 to 0:100). The pure fractions were collected and evaporated to dryness to give 1.1 g of intermediate 376 (68% yield).

Example A7 Preparation of Intermediate 387

In a round bottom flask, intermediate 372 (665.00 mg, 1.81 mmol) was diluted in DMF (7.29 mL). Then, NaH (60% dispersed in mineral oil) (79.70 mg, 1.99 mmol) was added and the mixture was become yellow. Then methyl methanesulfonate (1.84 mL, 21.73 mmol) was added and the reaction mixture was stirred at rt for 5 h. Then, a diluted solution of NH₄Cl was added and the aqueous layer was extracted twice with DCM and the combined layers were dried over MgSO₄. After filtration and careful removal of the solvent in vacuo, the residue (800 mg, yellow oil) was purified by column chromatography on silica gel (irregular SiOH, 40 g, mobile phase: heptane/EtOAc, gradient from 100:0 to 80:20). The fractions containing the product were collected and evaporated to dryness to give 573 mg of intermediate 387 (83% yield, colorless oil).

Preparation of Intermediate 388

N₂ was bubbled into a solution of intermediate 387 (50 mg, 0.13 mmol) and bis(pinacolato)diboron (41.60 mg, 0.16 mmol) in Me-THF (0.505 mL). [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane (5.35 mg, 0.066 mmol) and Pd(OAc)₂ (38.60 mg, 0.39 mmol) were added. The reaction mixture was degassed with N₂ and heated at 85° C. overnight. The reaction mixture was cooled to rt. The reaction mixture was filtered through a pad of Celite®. The organic layer was decanted and washed twice with water, brine, dried over MgSO₄, filtered and evaporated to dryness. The residue was used as it is for the next step (79% purity based on LC/MS).

Preparation of Intermediate 389

A solution of intermediate 388 (0.77 g, 1.79 mmol) in 1,4-dioxane (20 mL) was treated with Na₂CO₃ (2M, 2.68 mL, 5.36 mmol), 2,4-dichloropyrimidine (399.60 mg, 2.68 mmol) and Pd(PPh₃)₄ (103.30 mg, 0.09 mmol) and the mixture evacuated and purged thrice with N₂ and then heated to 80° C. overnight. The mixture was cooled and partitioned between EtOAc and water and the organic layer washed with water, brine, dried over Na₂SO₄ and evaporated to to dryness. The residue (1.15 g, brown oil) was purified by column chromatography on silica gel (irregular SiOH, 80 g, mobile phase: heptane/EtOAc, gradient from 100:0 to 80:20). The pure fractions were collected and evaporated to dryness to give 273 mg of intermediate 389 (37% yield, 79% purity based on LC/MS).

Example A8 Preparation of Intermediate 8

To a solution of intermediate 6 (0.15 g, 0.29 mmol), 3-amino-2-methoxypyridine (43.30 mg, 0.35 mmol), BINAP (18.10 mg, 30.00 μmol) and Cs₂CO₃ (284.00 mg, 0.87 mmol) in 1,4-dioxane (3 mL), Pd(OAc)₂ (6.51 mg, 30.00 μmol) was added and the reaction mixture was heated for 30 min at 85° C. The reaction mixture was left stirring at 95° C. for a further 1 h. The reaction mixture was then diluted with EtOAc, washed successively with water and brine. The organic layer was dried over Na₂SO₄ and concentrated in vacuo to give 235 mg of intermediate 8 as a dark brown oil used as it is in the next step.

The intermediates in the Table below were prepared by using an analogous method starting from the respective starting materials. The most relevant minor deviations to the referenced method are indicated as additional information in the column ‘Yield (%)’.

Intermediate number Structure Mass (mg) Yield (%) Intermediate 15

433 Quant. procedure with T = 95° C. Intermediate 17

1400 (60% purity based on LC/MS) brown solid 100 procedure with T = 95° C. Intermediate 22

110 (49% purity based on LC/MS) light yellow oil 340 (97% purity based on LC/MS) white powder 18             55 procedure with T = 95° C. Intermediate 23

524 yellow oil 80 procedure with T = 95° C. Intermediate 56

603 92 procedure with T = 120° C. Intermediate 62

532 (86% purity based on LC/MS) 77 procedure with T = 120° C. Intermediate 66

518 75 procedure with T = 120° C. Intermediate 70

518 79 Intermediate 72

281 48 procedure with T = 120° C. Intermediate 76

523 82 procedure with T = 120° C. Intermediate 80

511 78 procedure with T = 120° C. Intermediate 84

521 80 procedure with T = 120° C. Intermediate 88

476 74 procedure with T = 120° C. Intermediate 90

495 81 procedure with T = 120° C. Intermediate 94

430 67 procedure with T = 120° C. Intermediate 98

498 Quant. procedure with T = 100° C. Intermediate 102

441 (97% purity based on (LC/MS) 70 procedure with T = 120° C. Intermediate 104

450 (97% purity based on LC/MS) 72 procedure with T = 120° C. Intermediate 116

492 (73% purity based on LC/MS) yellow oil Quant. procedure with T = 95° C. Intermediate 120

607 92 procedure with T = 120° C. Intermediate 124

398 (94% purity based on LC/MS) 64 procedure with T = 120° C. Intermediate 132

571 87 procedure with T = 120° C. Intermediate 136

554 85 procedure with T = 120° C. Intermediate 140

685 pale yellow foam Quant. procedure with T = 100° C. Intermediate 144

504 (77% purity based on LC/MS) 81 procedure with T = 120° C. Intermediate 148

413 (91% purity based on LC/MS) — procedure with T = 120° C. Intermediate 156

467 (95% purity based on LC/MS) orange foam 89 procedure with T = 90° C. Intermediate 160

366 (99% purity based on LC/MS) orange foam 75 procedure with T = 90° C. Intermediant 163

1078 (82% purity based on LC/MS) 79 procedure with T = 120° C. Intermediate 176

534 orange foam 96 Intermediate 180

454 off-white foam — Intermediate 184

545 beige residue 76 procedure with T = 90° C. Intermediate 189

537 (93% purity based on LC/MS) Quant. procedure with T = 90° C. Intermediate 193

280 (59% purity based on LC/MS) brown oil — procedure with T = 90° C. Intermediate 195

587 (67% purity based on LC/MS) 66 procedure with T = 120° C. Intermediate 200

575 brown oil 89 procedure with T = 90° C. Intermediate 204

586 (93% purity based on LC/MS) 91 procedure with T = 120° C. Intermediate 208

509 (90% purity based on LC/MS) 76 procedure with T = 120° C. Intermediate 211

218 (89% purity based on LC/MS) 29 procedure with T = 120° C. Intermediate 216

323 (84% purity based on LC/MS) 37 procedure with T = 120° C. Intermediate 220

418 (92% purity based on LC/MS) 68 procedure with T = 120° C. Intermediate 227

1000 pale yellow oil 75 Intermediate 231

587 (98% purity based on LC/MS) white foam 79 Intermediate 235

1090 (88% purity based on LC/MS) pale yellow foam 87 Intermediate 248

701 (99% purity based on LC/MS) yellow solid 652 (60% purity based on LC/MS) yellow oil 59             33 Intermediate 251

967 (96% purity based on LC/MS) light yellow solid 73 Intermediate 273

457 (94% purity based on NMR) yellow foam 81 Intermediate 291

446 white foam 70 procedure with T = 90° C. Intermediate 297

484 (98% purity based on LCMS) pale yellow solid 91 Intermediate 300

405 (66% purity based on LCMS) orange solid 60 Intermediate 303

226 (92% purity based on LCMS) yellow solid 73 Intermediate 307

311 (74% purity based on LCMS) yellow solid 41 Intermediate 318

372 yellow foam 99 Intermediate 329

810 (84% purity based on LC/MS) brown gum Quant. Intermediate 362

2371 (96% purity based on LC/MS) yellow powder 64 Intermediate 401

360 foam Quant. procedure with T = 100° C. Intermediate 403

540 yellow solid 89 procedure with T = 95° C. Intermediate 405

720 — procedure with T = 95° C. Intermediate 407

272 foam 73 procedure with T = 100° C. Intermediate 409

610 grey solid 88 procedure with T = 100° C. Intermediate 411

688 yellow residue Quant. procedure with T = 95° C. Intermediate 413

308 (54% purity based on LC/MS) yellow oil 86 procedure with T = 95° C. Intermediate 417

748 yellow foam 83 procedure with T = 100° C. Intermediate 421

936 yellow foam 70 procedure with T = 100° C. Intermediate 425

400 (81% purity based on LC/MS) brown solid Quant. Intermediate 429

780 (77% purity based on LC/MS) yellow solid Quant. Intermediate 433

700 (71% purity based on LC/MS) brown solid Quant. Intermediate 437

235 pale yellow oil 44 Intermediate 439

800 (5% purity based on LC/MS) black foam Quant. Intermediate 443

414 yellow foam 77 Intermediate 545

144 70 procedure with T = 100° C. Intermediate 548

163 42 procedure with T = 120° C., 30 min μw Intermediate 567

600 88 procedure with T = 120° C., 3 h Intermediate 561

400 yellow solid 86 procedure with T = 120° C. Intermediate 551

625 (89% purity based on LC/MS) 68 Intermediate 529

300 (90% purity based on LC/MS) 54 procedure with T = 80° C. o/n Intermediate 572

360 yellow solid 20 procedure with T = 95° C. 2 h

Example A9 Preparation of intermediate 12

A degassed suspension of intermediate 6 (445.00 mg, 0.86 mmol), intermediate 11 (220.00 mg, 0.95 mmol), Pd(OAc)₂ (10.00 mg, 0.044 mmol), BINAP (27.00 mg, 0.043 mmol) and Cs₂CO₃ (844.00 mg, 2.59 mmol) in 1,4-dioxane (10 mL) was heated at 85° C. for 1 h 30 min. The reaction mixture was transferred in a MW sealed tube. Pd(OAc)₂ (5.00 mg, 0.020 mmol) and BINAP (14.00 mg, 0.022 mmol) were added and the reaction mixture was heated at 120° C. for 20 min using one single mode microwave (Biotage Initiator EXP 60) with a power output ranging from 0 to 400 W [fixed hold time]. The reaction mixture was cooled to rt, diluted with EtOAc and poured onto a 10% aqueous solution of K₂CO₃. The organic layer was decanted, washed with brine, dried over MgSO₄, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel (irregular SiOH, 40 g, mobile phase: heptane/MeOH/EtOAc, gradient from 0% MeOH, 40% EtOAc, 60% heptane to 2% MeOH, 58 EtOAc, 40% heptane). The pure fractions were collected and evaporated to dryness to give 390 mg of intermediate 12 (63% yield, 81% purity based on LC/MS). The intermediates in the Table below were prepared by using an analogous method starting from the respective starting materials. The most relevant minor deviations to the referenced method are indicated as additional information in the column ‘Yield (%)’.

Intermediate Mass number Structure (mg) Yield (%) Intermediate 26

535 85 procedure with T = 120° C. Intermediate 28

426 (81% purity based on LC/MS) 69 procedure With T = 120° C. Intermediate 30

534 (97% purity based on LC/MS) 87 procedure with T = 120° C. Intermediate 33

482 82 procedure with T = 120° C. Intermediate 39

397 77 procedure with T = 120° C. Intermediate 41

730 (85% purity based on LC/MS) brown foam Quant. procedure with T = 95° C. Intermediate 47

271 50 procedure with T = 120° C. Intermediate 50

421 79 procedure with T = 120° C. Intermediate 52

220 40 procedure with T = 120° C. Intermediate 58

310 66 procedure with T = 120° C. Intermediate 96

382 68 procedure with T = 120° C. Intermediate 107

425 67 procedure with T = 120° C. Intermediate 109

402 (95% purity based on LC/MS) 83 procedure with T = 120° C. Intermediate 111

276 59 procedure with T = 120° C. Intermediate 152

519 (94% purity based on LC/MS) 83 procedure with T = 120° C. Intermediate 168

276 (67% purity based on LC/MS) 40 procedure with T = 120° C. Intermediate 172

747 (87% purity based on LC/MS) Quant. procedure with T = 120° C. Intermediate 517

770 84 procedure with T = 120° C. 30 min Intermediate 525

620 Quant. procedure with T = 120° C. 30 min Intermediate 519

456 (90% purity based on LC/MS) Quant. procedure with T = 100° C. 2 h Intermediate 505

380 (83% purity based on LC/MS) 51 procedure with T = 80° C. o/n Intermediate 508

427 50 procedure with T = 120° C. 30 min μw Intermediate 587

425 73 Procedure with T = 120° C. 30 min μw

Example A10 Preparation of Intermediate 14

In a sealed tube, a mixture of intermediate 7 (400.00 mg, 0.96 mmol), 5-chloro-2-methoxypyridin-3-amine (168.00 mg, 1.06 mmol) and Cs₂CO₃ (942.00 mg, 2.89 mmol) in dry 1,4-dioxane (14 mL) was purged with N₂. Then, Pd(OAc)₂ (22.00 mg, 96.40 μmol) and BINAP (60.00 mg, 96.40 μmol) were added. The mixture was purged with N₂ and stirred at 95° C. for 2 h. The reaction mixture was combined with another batch (from 20 mg of int. 7) and the mixture was diluted with EtOAc and H₂O. The layers were separated. The organic layer was dried (MgSO₄), filtered and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (irregular SiOH 15-40 μm, 24 g, liquid injection (DCM), mobile phase: DCM/MeOH, gradient from 100:0 to 80:20). The pure fractions were combined and concentrated under vacuum to give 420 mg of intermediate 14 (77% yield, yellow solid).

The intermediates in the Table below were prepared by using an analogous method starting from the respective starting materials. The most relevant minor deviations to the referenced method are indicated as additional information in the column ‘Yield (%)’.

Intermediate number Structure Mass (mg) Yield (%) Intermediate 46

281 — Intermediate 162

2070 (99% purity based on LC/MS) 56 procedure with T = 120° C. Intermediate 223

352 (99% purity based on LC/MS) 49 procedure with T = 120° C. Intermediate 255

389 (91% purity based on LC/MS) 65 procedure with T = 120° C. Intermediate 258

93 38 procedure with T = 120° C. Intermediate 261

186 (58% purity based on LC/MS) 70 procedure with T = 120° C. Intermediate 264

231 83 procedure with T = 120° C. Intermediate 267

90 46 procedure with T = 120° C. Intermediate 279

458 (80% purity based on LC/MS) off-white solid 78 procedure with T = 85° C. Intermediate 285

36 yellow oil 10 procedure with T = 85° C. Intermediate 288

146 43 procedure with T = 120° C. Intermediate 314

449 (91% purity based on LC/MS) 70 procedure with T = 120° C. Intermediate 398

236 orange oil 57 procedure with T = 95° C. Intermediate 399

220 brown residue 45 procedure with T = 95° C. Intermediate 400

268 brown oil 67 with T = 95° C. Intermediate 470

135 40 procedure with T = 120° C. 5 h Intermediate 449

91 yellow oil 33 procedure with T = 120° C. 3 h Intermediate 451

163 yellow solid 56 procedure with T = 120° C. 3 h Intermediate 477

307 65 procedure with T = 120° C. 4 h Intermediate 465

394 72 procedure with T = 120° C. 3 h Intermediate 467

210 41 procedure with T = 120° C. 3 h Intermediate 456

180 75 procedure with T = 120° C. 3 h Intermediate 458

90 yellow oil 46 procedure with T = 120° C. 3 h Intermediate 479

125 41 procedure with T = 120° C. 3 h Intermediate 502

221 35 procedure with T = 120° C. 3 h Intermediate 497

470 72 procedure with T = 120° C. 15 min, μw Intermediate 473

100 45 procedure with T = 120° C. 3 h Intermediate 558

47 65 procedure with T = 100° C. 6 h Intermediate 492

428 (81% purity based on LC/MS) 78 procedure with T = 120° C. 30 min, μw Intermediate 494

598 75 procedure with T = 120° C. 30mn, μw Intermediate 512

662 52 procedure with T = 120° C. 1 h Intermediate 560

100 32 procedure with T = 120° C. μw 30 min Intermediate 539

10 7 procedure with T = 120° C. 3 h Intermediate 536

248 (80% purity based on LC/MS) 39 procedure with T = 120° C. 15 min μw Intermediate 540

188 52 procedure with T = 120° C. 3 h Intermediate 534

1280 66 procedure with T = 120° C. 3 h Intermediate 532

160 92 procedure with T = 120° C. 3 h Intermediate 586

77 31 procedure with T = 120° C. 4 h

Example A11 Preparation of Intermediate 20

A mixture of intermediate 6 (300.00 mg, 0.58 mmol), 3-amino-2,5-dichloropyridine (237.00 mg, 1.46 mmol) and Cs₂CO₃ (569.00 mg, 1.75 mmol) in THF (6 mL) was purged with N₂. Then (BrettPhos) palladium (II) phenethylamine chloride (47.00 mg, 58.20 μmol) and BrettPhos (31.00 mg, 58.20 μmol) were added. The mixture was purged with N₂ and stirred at 95° C. for 18 h. An extraction was performed with AcOEt and water. The organic layer was washed with brine, dried and evaporated to give 450 mg of intermediate 20 (quant. yield, black solid) used as such for the next step.

The intermediates in the Table below were prepared by using an analogous method starting from the respective starting materials.

Intermediate number Structure Mass (mg) Yield (%) Intermediate 395

800 (62% purity based on LC/MS) brown solid Quant. procedure with THF as solvent

Example A12 Preparation of Intermediate 13

A solution of TBAF (1.0 M in THF) (576.00 μL, 0.58 mmol) was added to a solution of intermediate 12 (390.00 mg, 0.55 mmol) in Me-THF (5 mL) and the mixture was stirred at rt for 1 h. The reaction mixture was poured onto a 10% aqueous solution of K₂CO₃ and extracted with EtOAc. The organic layer was decanted, washed with brine, dried over MgSO₄, filtered and evaporated to dryness. The residue was taken up with Et₂O and the precipitate was filtered and dried to give 274 mg of intermediate 13 (84% yield, 98% purity based on LC/MS).

The intermediates in the Table below were prepared by using an analogous method starting from the respective starting materials. The most relevant minor deviations to the referenced method are indicated as additional information in the column ‘Yield (%)’.

Intermediate number Structure Mass (mg) Yield (%) Intermediate 16

355 black oil Quant. procedure with THF as solvent Intermediate 19

360 yellow solid — procedure with THF as solvent Intermediate 21

420 (73% purity based on LC/MS) black oil Quant. procedure with THF as solvent Intermediate 29

290 (98% purity based on LC/MS) 81 Intermediate 57

449 89 procedure with 3 equiv. of TBAF Intermediate 71

295 69 procedure with 3 equiv. of TBAF Intermediate 73

200 88 procedure with 3 equiv. of TBAF Intermediate 164

622 71 Intermediate 190

420 yellow oil 93 Intermediate 194

190 (85% purity based on LC/MS) yellow oil — Intermediate 201

386 (96% purity based on LC/MS) brown oil 80 Intermediate 209

300 71 procedure with 2 equiv. of TBAF Intermediate 212

165 95 procedure with 2 equiv. of TBAF Intermediate 217

236 (95% purity based on LC/MS) 88 procedure with 2 equiv. of TBAF Intermediate 221

269 78 procedure with 2 equiv. of TBAF Intermediate 228

600 yellow foam 76 Intermediate 359

2200 yellow solid — procedure with THF as solent with 2 equiv.of TBAF Intermediate 363

1680 (96% purity based on LC/MS) red powder 86 procedure with THF as solent with 2 equiv.of TBAF Intermediate 426

40 yellow solid 14 Intermediate 430

418 white foam (87% purity based on NMR) 72 Intermediate 434

295 pale yellow foam 70 procedure with 1.8 equiv.of TBAF Intermediate 440

432 white solid 86 procedure with 1.7 equiv. of TBAF Intermediate 573

260 yellow solid 98 procedure with 7.8 equiv. of TBAF 30 min

Example A13 Preparation of Intermediate 59

TBAF (on silica gel 1.5 mmol/g) (2.22 g, 3.33 mmol) was added to a solution of intermediate 58 (335.00 mg, 0.56 mmol) in Me-THF (15 mL) and the reaction mixture was stirred at rt for 18 h. The reaction mixture was diluted with DCM, filtered through paper and poured onto a 10% aqueous solution of K₂CO₃. The organic layer was decanted, washed with water, dried over MgSO₄, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel (irregular SiOH, 24 g, mobile phase: DCM/MeOH, gradient from 97:3 to 92:8). The pure fractions were collected and evaporated to dryness to give 196 mg of intermediate 59 (72% yield).

The intermediates in the Table below were prepared by using an analogous method starting from the respective starting materials. The most relevant minor deviations to the referenced method are indicated as additional information in the column ‘Yield (%)’.

Intermediate number Structure Mass (mg) Yield (%) Intermediate 77

278 64 Intermediate 81

298 70 Intermediate 85

334 77 Intermediate 89

247 63 Intermediate 91

287 71 Intermediate 95

265 74 Intermediate 112

166 79 Intermediate 121

345 68 Intermediate 196

265 84 procedure with 4 equiv. of TBAF Intermediate 205

254 79 procedure with 4 equiv. of TBAF

Example A14 Preparation of Intermediate 18

A mixture of intermediate 17 (1.40 g, 1.35 mmol) in TFA (3 mL) and DCM (15 mL) was stirred at rt for 1 h 30 min. The mixture was basified with saturated aq. NaHCO₃. An extraction was performed with DCM. The organic layer was washed with brine, dried over MgSO₄, evaporated and purified by column chromatography on silica gel (irregular SiOH 15-40 μm, 120 g, liquid injection (DCM), mobile phase: heptane/AcOEt, gradient from 100:0 to 0:100 in 15 CV). The fractions containing the product was concentrated under vacuum to give 480 mg of intermediate 18 (68% yield, yellow solid).

The intermediates in the Table below were prepared by using an analogous method starting from the respective starting materials. The most relevant minor deviations to the referenced method are indicated as additional information in the column ‘Yield (%)’.

Intermediate Mass number Structure (mg) Yield (%) Intermediate 27

452 Quant. procedure with DCM/ TFA (5:2, v/v) Intermediate 31

176 41 procedure with DCM/ TFA (31:1, v/v) Intermediate 34

144 37 procedure with DCM/ TFA (32:1, v/v) Intermediate 40

132 (90% purity based on LC/MS) 39 procedure with DCM/ TFA (33:1, v/v) Intermediate 42

274 52 Intermediate 48

144 68 procedure with DCM/ TFA (10:1, v/v) Intermediate 51

191 54 procedure with DCM/ TFA (10:1, v/v) Intermediate 53

117 65 procedure with DCM/ TFA (10:1, v/v) Intermediate 63

230 50 procedure with DCM/ TFA (31:1, v/v) Intermediate 67

273 (78% purity based on LC/MS) 63 procedure with DCM/ TFA (31:1, v/v) Intermediate 97

250 86 procedure with DCM/ TFA (32:1, v/v) Intermediate 99

366 Quant. procedure with DCM/ TFA (4:1, v/v) Intermediate 103

315 86 procedure with DCM/ TFA (32:1, v/v) Intermediate 105

342 91 procedure with DCM/ TFA (32:1, v/v) Intermediate 108

239 71 procedure with DCM/ TFA (31:1, v/v) Intermediate 110

285 85 procedure with DCM/ TFA (9:1, v/v) Intermediate 117

252 (85% purity based on LC/MS) 59 procedure with DCM/ TFA (2:1, v/v) Intermediate 125

221 (66% purity based on LC/MS) 66 procedure with DCM/ TFA (17:1, v/v) Intermediate 133

343 71 procedure with DCM/ TFA (10:1, v/v) Intermediate 137

351 74 procedure with DCM/ TFA (10:1, v/v) Intermediate 141

301 yellow foam 38 procedure with DCM/ TFA (10:1, v/v) Intermediate 145

150 35 procedure with DCM/ TFA (17:1, v/v) Intermediate 149

219 63 procedure with DCM/ TFA (20:1, v/v) Intermediate 153

169 39 procedure with DCM/ TFA (17:1, v/v) Intermediate 157

273 (96% purity based on NMR) 69 procedure with DCM/ TFA (10:1, v/v) Intermediate 161

237 (91% purity based on NMR) colorless oil 69 procedure with DCM/ TFA (10:1, v/v) Intermediate 173

635 (62% purity based on LC/MS) Quant. procedure with DCM/ TFA (17:1, v/v) Intermediate 169

116 (65% purity based on LC/MS) 49 procedure with DCM/ TFA (17:1, v/v) Intermediate 177

351 orange foam — procedure with DCM/ TFA (10:1, v/v) Intermediate 181

275 off- white foam — procedure with DCM/ TFA (12:1, v/v) Intermediate 185

276 59 procedure with DCM/ TFA (4:1, v/v) Intermediate 232

411 (90% purity based on LC/MS) off- white foam — procedure with DCM/ TFA (10:1, v/v) Intermediate 236

422 (90% purity based on LC/MS) pale yellow oil 46 procedure with DCM/ TFA (10:1, v/v) Intermediate 249

505 (85% purity based on LC/MS) yellow solid 85 procedure with DCM/ TFA (10:1, v/v) Intermediate 252

717 (80% purity based on NMR) yellow oil 70 procedure with DCM/ TFA (10:1, v/v) Intermediate 274

277 white foam 76 procedure with DCM/ TFA (10:1, v/v) Intermediate 298

280 (96% purity based on LC/MS) pale yellow solid 72 procedure with DCM/ TFA (10:1, v/v) Intermediate 301

280 (80% purity based on NMR) pale yellow solid 63 procedure with DCM/ TFA (10:1, v/v) Intermediate 304

136 yellow solid 72 procedure with DCM/ TFA (10:1, v/v) Intermediate 308

179 (85% purity based on NMR) pale yellow solid — procedure with DCM/ TFA (10:1, v/v) Intermediate 330

441 yellow solid 73 procedure with DCM/ TFA (10:1, v/v) Intermediate 396

50 (100% purity based on LC/MS) white solid 12 procedure with DCM/ TFA (8:3, v/v) Intermediate 402

147 white solid 50 procedure with DCM/ TFA (10:1, v/v) Intermediate 404

450 brown oil Quant. procedure with DCM/ TFA (8:3, v/v) Intermediate 406

590 brown oil — procedure with DCM/ TFA (8:3, v/v) Intermediate 408

139 (90% purity based on LC/MS) yellow solid 62 procedure with DCM/ TFA (10:1, v/v) Intermediate 410

478 91 procedure with DCM/ TFA (10:1, v/v) Intermediate 412

246 off- white solid 44 procedure with DCM/ TFA (4:1, v/v) Intermediate 414

470 — procedure with DCM/ TFA (5:2, v/v) Intermediate 418

470 (98% purity based on LC/MS) 50 procedure with DCM/ TFA (10:1, v/v) Intermediate 422

370 yellow foam 48 procedure with DCM/ TFA (10:1, v/v) Intermediate 438

87 off- white foam 43 procedure with DCM/ TFA (10:1, v/v) Intermediate 444

188 white foam 53 procedure with DCM/ TFA (10:1, v/v) Intermediate 520

378 100 procedure with DCM/ TFA (12:1, v/v) Intermediate 506

280 (49% purity based on LC/MS) 47 procedure with DCM/ TFA (5:1, v/v) Intermediate 530

435 (65% purity based on LC/MS) 100% procedure with DCM/ TFA (6:1, v/v) Intermediate 588

277 92 procedure with DCM/ TFA (17:1, v/v) 5° C.; 1 h

Example A15 Preparation of Intermediate 292

In a sealed tube, SiO₂ (40-63 μm) (1.00 g, 5 equiv. wt) was added to a solution of intermediate 291 (200.00 mg, 0.30 mmol) in toluene (2 mL). The mixture was refluxed for 2 h. Some Celite® was added and the resulting mixture was evaporated in vacuo. The residue was purified by column chromatography on silica gel (irregular SiOH 15-40 μm, grace 80 g, dry loading, mobile phase: heptane/AcOEt, gradient: from 70:30 to 30:70 in 10 CV). The pure fractions were combined and evaporated to dryness to give 160 mg of intermediate 292 (94% yield, white solid).

The intermediates in the Table below were prepared by using an analogous method starting from the respective starting materials.

Mass Yield Intermediate number Structure (mg) (%) Intermediate 319

49 16 From intermediate 318 Intermediate 518

497 76 From intermediate 517 Intermediate 509

287 80 From intermediate 508 Intermediate 546 CIS mixture (RS and SR)  

108 87 LC- MS: 95% From intermediate 545 Intermediate 549

124 90 From intermediate 548 Intermediate 568 TRANS mixture (RR and SS)  

500 97 LC- MS: 60% From intermediate 567 Intermediate 562

320 95 From intermediate 561 Intermediate 552

640  100% From intermediate 551

Example A16 Preparation of Intermediate 335

A degassed suspension of intermediate 334 (73.00 mg, 0.19 mmol), 3-amino-2-methoxy pyridine (26.10 mg, 0.21 mmol), Pd(OAc)₂ (4.27 mg, 0.019 mmol), BINAP (11.83 mg, 0.019 mmol) and Cs₂CO₃ (185.72 mg, 0.57 mmol) in 1,4-dioxane (2 mL) was heated to 85° C. for 1 h. The reaction mixture was partitioned between EtOAc and diluted with a solution of NaHCO₃. The organics layers were washed with brine, dried over Na₂SO₄ and concentrated in vacuo. This residue (89 mg, quant. yield, 73% purity based on LC/MS) was used in the next step without further purification.

The intermediates in the Table below were prepared by using an analogous method starting from the respective starting materials.

Intermediate number Structure Mass (mg) Yield (%) Intermediate 336

150 brown oil Quant. From intermediate 334 and intermediate 11 Intermediate 340

171 brown oil Quant. From intermediate 334 and intermediate 339 Intermediate 397

340 (98% purity based on LC/MS) 83 From intermediate 334 and 2-(4- morpholinyl)-5-Pyrimidinamine Intermediate 578

200 (88% purity based on LC/MS) 89 procedure with T = 95° C. 2h From intermediate 334 and intermediate 577

Example A17 Preparation of Intermediate 344

Intermediate 343 (0.35 g, 0.66 mmol), 3-amino-2-methoxypyridine (81.50 mg, 0.66 mmol) and Cs₂CO₃ (0.64 g, 1.97 mmol) in 1,4-dioxane (6.3 mL) was degassed with N₂. Then, Pd(OAc)₂ (14.70 mg, 0.066 mmol) and BINAP (40.88 mg, 0.066 mmol) were added together and the resulting mixture was heated at 120° C. for 20 min using one single mode microwave (Biotage Initiator EXP 60) with a power output ranging from 0 to 400 W [fixed hold time]. The reaction mixture was cooled down to rt, and partitionned between water and EtOAc. The organic layer was separated, dried over MgSO₄ and concentrated. The residue was purified by column chromatography on silica gel (irregular SiO₂, 40 g, mobile phase: heptane/EtOAc, gradient from 9:1 to 0:1). The fractions containing the products were mixed and the solvent was concentrated to give 0.408 g of intermediate 344 (100% yield, 92% purity based on LC/MS).

The intermediates in the Table below were prepared by using an analogous method starting from the respective starting materials. The most relevant minor deviations to the referenced method are indicated as additional information in the column ‘Yield (%)’.

Intermediate number Structure Mass (mg) Yield (%) Intermediate 346

552 (75% purity based on LC/MS) 96 procedure without microwave activation From intermediate 343 and 5-chloro- 2-methoxypyridine-3-amine Intermediate 349

378 (97% purity based on LC/MS) 93 From intermediate 348 and 3-amino- 2-methoxypyridine Intermediate 351

402 (65% purity based on LC/MS) 61 procedure without microwave activation with T = 95° C. From intermediate 348 and 5-chloro- 2-methoxypyridine-3-amine Intermediate 353

429 (95% purity based on LC/MS) 83 procedure without microwave activation From intermediate 343 and intermediate 65 Intermediate 355

442 75 procedure without microwave activation From intermediate 348 and intermediate 101 Intermediate 357

430 66 procedure without microwave activation From intermediate 348 and intermediate 69

Example A18 Preparation of Intermediate 345

TFA (0.82 mL) was added at 5° C. to a solution of intermediate 344 (443.00 mg, 0.71 mmol) in DCM (7 mL). The reaction mixture was stirred at 5° C. for 1 h. The mixture was diluted with DCM (50 mL) and poured onto a 10% aqueous solution of K₂CO₃. More DCM/MeOH was added (80:20, 200 mL) The organic layer was decanted, washed with a 10% aqueous solution of K₂CO₃, dried over MgSO₄, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel (15-40 μm, 40 g, mobile phase: heptane/EtOAc/MeOH, gradient from 100:0:0 to 80:20:0 to 0:98:2). The pure fractions were collected and evaporated to dryness to give 0.248 g of intermediate 345 (67% yield).

The intermediates in the Table below were prepared by using an analogous method starting from the respective starting materials. The most relevant minor deviations to the referenced method are indicated as additional information in the column ‘Yield (%)’.

Intermediate number Structure Mass (mg) Yield (%) Intermediate 347

86 (89% purity based on LC/MS) 23 From intermediate 346 Intermediate 350

213 (98% purity based on LC/MS) 67 From intermediate 349 Intermediate 352

216 (83% purity based on LC/MS) 64 From intermediate 351 Intermediate 354

276 75 procedure with DCM/TFA (31:1, v/v) From intermediate 353 Intermediate 356

316 (87% purity based on LC/MS) 84 procedure with DCM/TFA (31:1, v/v) From intermediate 355 Intermediate 358

247 67 procedure with DCM/TFA (17:1, v/v) From intermediate 357 Intermediate 526

340 65% procedure with DCM/TFA (6:1, v/v) with T = 0° C. 30 min From intermediate 525

Example A19 Preparation of Intermediate 360

A dry three neck round bottom flask (25 mL) was charged with DCM (1 mL), cooled to −78° C., and oxalyl chloride (2.55 mL, 5.11 mmol) was added followed by DMSO (0.73 mL, 10.21 mmol). After 1 h, a solution of intermediate 359 (1.66 g, 3.40 mmol) in solution in DCM (4 mL) was added dropwise. The mixture was stirred for 1 h at −78° C., before DIPEA (3.52 mL, 20.42 mmol) was added. Stirring was continued and then the mixture was allowed to warn to rt over 5 h. A diluted solution of NH₄Cl was added and the aqueous layer was extracted twice with DCM and the combined layers were dried with MgSO₄. After filtration and careful removal of the solvent in vacuo, 1.73 g of intermediate 360 was obtained (14% purity based on LC/MS, yellow solid).

Preparation of Intermediate 365

A solution of intermediate 360 (0.20 g, 0.41 mmol), cyclopropylamine (0.30 mL, 4.93 mmol), AcOH (141.00 μL, 2.47 mmol) and NaBH(OAc)₃ (87.20 mg, 4.11 mmol) in dichloroethane (8.3 mL) was stirred at rt over the weekend. A saturated NaHCO₃ solution was added and the aqueous layer was extracted with DCM. The organic layer was dried over MgSO₄ and evaporated to dryness. The residue (420 mg, colorless oil) was purified by column chromatography on silica gel (irregular SiOH, 24 g, mobile phase: heptane/EtOAc, gradient from 100:0 to 60:40). The fractions containing the product were evaporated to provide 139 mg of intermediate 365 (64% yield, 98% purity based on LC/MS, colorless oil).

The intermediates in the Table below were prepared by using an analogous method starting from the respective starting materials. The most relevant minor deviations to the referenced method are indicated as additional information in the column ‘Yield (%)’.

Intermediate number Structure Mass (mg) Yield (%) Intermediate 361

93 white solid 45 From intermediate 360 and methylamine Intermediate 366

126 (99% purity based on LC/MS) white powder 278 (98% purity based on LC/MS) colorless oil 16 34 From intermediate 360 and N-Boc piperazine Intermediate 367

172 colorless oil 47 From intermediate 360 and 2- (methylsulfonyl)ethanamine Intermediate 368

82 colorless oil 24 From intermediate 360 and morpholine Intermediate 369

154 (87% purity based on LC/MS) colorless oil 41 From intermediate 360 and 2-[[(1,1- dimethylethyl)dimethylsilyl]oxy]-N- methyl-ethanalamine Intermediate 370

630 (81% purity based on LC/MS) yellow oil 86 From intermediate 360 and 2,4- dimethoxybenzylamine

Example A20 Preparation of intermediate 364

To a solution of intermediate 363 (0.20 g, 0.38 mmol) and L-BOC-alanine (79.60 mg, 0.42 mmol) in DCM (0.64 mL) at 0° C., HATU (523.50 mg, 1.38 mmol), DIPEA (132.00 μL, 0.76 mmol) and DMAP (2.34 mg, 19.10 μmol) were added. The resulted mixture was stirred at rt over the weekend. The organic layer was washed with 1 N HCl, water and brine, dried over MgSO₄, filtered and evaporated to provide a purple oil. The residue (300 mg) was purified by column chromatography on silica gel (Irregular SiOH, 12 g, mobile phase: heptane/EtOAc, gradient from 100:0 to 60:40). The fractions containing the products were combined and evaporated to provide 270 mg of intermediate 364 (Quant. yield, white powder).

Example A21 Preparation of Intermediate 371

To a solution of intermediate 370 (630.00 mg, 0.99 mmol) in CH₃CN (3.1 mL), Ac₂O (0.103 mL, 1.09 mmol) and pyridine (88.00 μL, 1.09 mmol) were added and stirring overnight. The mixture was concentrated to dryness. The residue was purified by column chromatography on silica gel (irregular SiOH, 40 g, mobile phase: NH₄OH/DCM/MeOH, gradient from 100% DCM to 95% DCM 5% MeOH, 0.5% NH₄OH). Fractions containing the products were collected and evaporated to dryness to give three batches as a colorless oil (batch 1: 42 mg, batch 2: 15 mg, batch 3: 727 mg). Batch 3 was purified another time by column chromatography on silica gel (irregular SiOH, 40 g, mobile phase: heptane/EtOAc/MeOH, gradient from 100% Heptane 0% EtOAc 1% MeOH to 0% Heptane 100% EtOAc 1% MeOH). The fractions containing the product were gathered and evaporated to dryness to provide 457 mg of intermediate 371 (68% yield, 86% purity based on LC/MS, yellow oil) and 79 mg of intermediate 371 (12% yield, 93% purity based on LC/MS, white powder).

Example A22 Preparation of Intermediate 377

A degassed suspension of intermediate 376 (339.00 mg, 0.76 mmol), 2-methoxypyridin-3-amine (189.20 mg, 1.52 mmol), Pd(OAc)₂ (8.50 mg, 0.038 mmol), BINAP (23.70 mg, 0.038 mmol) and Cs₂CO₃ (744.80 mg, 2.29 mmol) in 1,4-dioxane (10 mL) was heated at 120° C. for 30 min using one single mode microwave (Biotage Initiator EXP 60) with a power output ranging from 0 to 400 W [fixed hold time]. The reaction mixture was cooled to rt, diluted with EtOAc and poured onto a 10% aqueous solution of K₂CO₃. The organic layer was decanted, washed with brine, dried over MgSO₄, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel (irregular SiOH, 24 g, mobile phase: heptane/EtOAc/MeOH, gradient from 20% EtOAc, 80% heptane to 1% MeOH, 60% EtOAc, 39% heptane). The pure fractions were collected and evaporated to dryness to give 350 mg of intermediate 377 (86% yield, 95% purity based on LC/MS).

The intermediates in the Table below were prepared by using an analogous method starting from the respective starting materials. The most relevant minor deviations to the referenced method are indicated as additional information in the column ‘Yield (%)’.

Intermediate number Structure Mass (mg) Yield (%) Intermediate 382

1200 (93% purity based on LC/MS) 65 procedure without microwave activation From intermediate 376 and 2- methoxy-4-chloropyridin-3- amine

Preparation of Intermediate 378

MsCl (41.00 μL, 0.53 mmol) was added dropwise at 5° C. to a solution of intermediate 377 (237.00 mg, 0.44 mmol) and TEA (148.00 μL, 1.07 mmol) in DCM (5 mL) and the reaction mixture was stirred at this temperature for 1 h. The reaction mixture was diluted with DCM and water was added. The organic layer was filtered through Chromabond® and evaporated to dryness to give 298 mg of intermediate 378 (quant. yield) and used as it is for the next step.

The intermediates in the Table below were prepared by using an analogous method starting from the respective starting materials.

Intermediate number Structure Mass (mg) Yield (%) Intermediate 383

1360 Quant. From intermediate 382

Preparation of Intermediate 379

A mixture of intermediate 378 (270.00 mg, 0.44 mmol) and isopropylamine (1.90 mL, 22.11 mmol) in CH₃CN (5 mL) was heated at 80° C. for 3 h. The reaction mixture was gathered with another batch (from 55 mg of intermediate 378) for the work up. The resulting crude mixture was diluted with DCM and poured onto water. The organic layer was decanted, dried over MgSO₄, filtered and evaporated to dryness to give 282 mg of intermediate 379 (92% yield, 98% purity based on LC/MS) used as it is for the next step.

The intermediates in the Table below were prepared by using an analogous method starting from the respective starting materials.

Intermediate number Structure Mass (mg) Yield (%) Intermediate 380

402 88 From intermediate 378 and morpholine Intermediate 381

395 89 From intermediate 378 and pyrrolidine Intermediate 384

358 (98% purity based on LC/MS) 84 From intermediate 383 and cyclopropylamine Intermediate 385

340 (99% purity based on LC/MS) 78 From intermediate 383 and pyrrolidine Intermediate 386

400 (91% purity based on LC/MS) 90 From intermediate 383 and morpholine

Example A23 Preparation of Intermediate 390

A mixture of intermediate 389 (0.27 g, 0.65 mmol), Cs₂CO₃ (636.10 mg, 1.95 mmol) and 3-amino-5-chloropicoline (139.20 mg, 0.98 mmol) in 1,4-dioxane (6.70 mL) was purged with N₂. Then Pd(OAc)₂ (14.60 mg, 0.065 mmol) and BINAP (40.50 mg, 0.065 mmol) were added. The mixture was purged with N₂ and stirred at 90° C. for 9 h. An extraction was performed with EtOAc and water. The organic layer was washed with brine, dried and evaporated to give a black oil. The residue (450 mg) was purified on silica gel (irregular SiOH, 40 g, mobile phase: heptane/EtOAc/MeOH, gradient from 0% EtOAc, 100% heptane to 60% EtOAc, 40% heptane, 1% MeOH). The fractions containing the product were collected and evaporated to dryness to give 201 mg of intermediate 390 (59% yield, 95% purity based on LC/MS, yellow oil).

Example A24 Preparation of Intermediate 9

A mixture of 6-chloro-2-methoxy-3-nitropyridine (0.50 g, 2.65 mmol), 2-methoxyethanolamine (277.00 μL, 3.19 mmol) and DIPEA (1.40 mL, 8.04 mmol) in 2-propanol (5 ml) was heated at 120° C. for 30 min using one single mode microwave (Biotage Initiator EXP 60) with a power output ranging from 0 to 400 W for 15 min [fixed hold time]. The reaction mixture was cooled to rt, partitioned between water and EtOAc. The organic layer was dried over MgSO₄, filtered and concentrated to afford 460 mg of intermediate 9 (76% yield) which was directly engaged in the next step without any further purification.

The intermediates in the Table below were prepared by using an analogous method starting from the respective starting materials.

Intermediate Mass Yield number Structure (mg) (%) Intermediate 36

 885 67 From intermediate 35 Intermediate 113

 780 76 6-chloro-2-methoxy-3- nitropyridine Intermediate 165

2630 91 2-fluoro-5-nitro-6-picoline

Preparation of Intermediate 10

A mixture of intermediate 9 (1.00 g, 4.40 mmol) and NCS (705.00 mg, 5.28 mmol) in CH₃CN (13 mL) was heated at 85° C. for 30 min using one single mode microwave (Biotage Initiator EXP 60) with a power output ranging from 0 to 400 W [fixed hold time]. The reaction was performed three times on the same quantity of intermediate 9 (1.00, 4.40 mmol; 3.00 g, 13.20 mmol). The reaction mixtures were combined and partitioned between water and EtOAc. The organic layer was decanted, dried over MgSO₄, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel (irregular SiOH, 40 g, mobile phase: heptane/MeOH/EtOAc, gradient from 0% MeOH, 30% EtOAc, 70% heptane to 2% MeOH, 48% EtOAc, 50% heptane). The pure fractions were collected and evaporated to dryness to give 1.9 g of intermediate 10 (55% yield).

The intermediates in the Table below were prepared by using an analogous method starting from the respective starting materials

Intermediate number Structure Mass (mg) Yield (%) Intermediate 37

459 66 From intermediate 36 Intermediate 114

990 yellow oil — From intermediate 113 Intermediate 166

2950 yellow oil Quant. From intermediate 165

Preparation of Intermediate 11

A mixture of intermediate 10 (500.00 mg, 1.91 mmol), NH₄Cl (409.00 mg, 7.64 mmol) and Iron powder (534.00 mg, 9.55 mmol) in EtOH (6 mL) and distilled water (9 mL) was heated at 75° C. for 1 h. The reaction mixture was cooled to rt, diluted with DCM and filtered through a pad of Celite®. The solution was poured onto a 10% aqueous solution of K₂CO₃. The organic layer was decanted, dried over MgSO₄, filtered and evaporated to dryness to give 456 mg of intermediate 11 used immediately as it is for the next step.

The intermediates in the Table below were prepared by using an analogous method starting from the respective starting materials. The most relevant minor deviations to the referenced method are indicated as additional information in the column ‘Yield (%)’.

Intermediate number Structure Mass (mg) Yield (%) Intermediate 32

 206 95 From intermediate 9 Intermediate 38

198 (>97% purity based on LC/MS) 98 From intermediate 37 Intermediate 49

 600 Quant. From 2-methoxy-3-nitropyridine Intermediate 55

1026 77 From intermediate 54 Intermediate 61

1668 91 From intermediate 60 Intermediate 65

1096 93 From intermediate 64 Intermediate 69

1569 (85% purity based on NMR) 1334 43 31 From intermediate 68 Intermediate 75

1150 93 From intermediate 74 Intermediate 79

 768 95 From intermediate 78 Intermediate 83

 727 89 From intermediate 82 Intermediate 87

1040 91 From intermediate 86 Intermediate 93

 940 Quant. From intermediate 92 Intermediate 101

1650 76 From intermediate 100 Intermediate 106

 298 70 From 5-chloro-2-ethoxy-3- nitropyridine Intermediate 115

 438 55 procedure with T = 85° C. From intermediate 114 Intermediate 119

536 (82% purity based on LC/MS) 80 From intermediate 118 Intermediate 123

 606 97 From intermediate 122 Intermediate 131

 649 92 From intermediate 122 Intermediate 135

 884 94 From intermediate 134 Intermediate 143

 882 97 From intermediate 142 Intermediate 147

 207 94 From intermediate 146 Intermediate 151

 484 Quant. From intermediate 150 Intermediate 155

224 brown solid 91 procedure with T = 85° C. From intermediate 154 Intermediate 167

1637 (95% purity based on LC/MS) brown oil 63 From intermediate 166 Intermediate 171

 725 78 From intermediate 170 Intermediate 183

228 brown oil 77 procedure with T = 85° C. From intermediate 182 Intermediate 203

 489 95 From intermediate 202 Intermediate 207

 435 90 From intermediate 206 Intermediate 254

 230 87 From intermediate 253 Intermediate 257

 78 68 From intermediate 256 Intermediate 260

 102 48 From intermediate 259 Intermediate 263

160 (80% purity based on LC/MS) 100 From intermediate 262 Intermediate 266

94 (85% purity based on LC/MS) 59 From intermediate 265 Intermediate 287

108 (99% purity based on LC/MS) 77 From intermediate 286 Intermediate 339

68 (90% purity based on LC/MS) dark purple oil 76 From intermediate 338

Example A25 Preparation of Intermediate 35

NaH (60% dispersed in mineral oil) (269.00 mg, 6.7 mmol) was added portionwise at 5° C. to a solution of 2,6-dichloro-3-nitropyridine (1.00 g, 5.18 mmol) and iPrOH (476.00 μL, 6.22 mmol) in toluene (50 mL). The reaction mixture was allowed to warm to rt and stirred overnight. The reaction mixture was poured onto a 10% aqueous solution of K₂CO₃ and extracted thrice with EtOAc. The organic layer was decanted, washed with brine, dried over MgSO₄, filtered and evaporated to dryness to give 1.15 g of intermediate 35 (quant. yield).

The intermediates in the Table below were prepared by using an analogous method starting from the respective starting materials.

Intermediate number Structure Mass (mg) Yield (%) Intermediate 43

385 brown oil —

Example A26 Preparation of Intermediate 44

Intermediate 43 (385.00 mg, 1.42 mmol) was diluted in EtOAc (10.5 mL), and platinum (553.00 mg, 142.00 μmol) and ZnBr₂ (64.00 mg, 284.00 μmol) were added. The mixture was hydrogenated under an atmosphere of H₂ (1 bar) at rt for 17 h. The reaction mixture was filtered on a pad of Celite® and the filtrate was concentrated under reduced pressure to give 290 mg of intermediate 44 (85% yield, 95% purity based on LC/MS).

Example A27 Preparation of Intermediate 54

3-hydroxytetrahydrofuran (869.00 μL, 10.56 mmol) was diluted in THF (33.5 mL). Then, the solution was cooled to 0° C. and LiHMDS (10.00 mL, 10.56 mmol) was added. After 30 min, 2-fluoro-3-nitropyridine (1.50 g, 10.56 mmol) was quickly added and the reaction mixture was stirred overnight allowing the temperature to reach rt. The reaction mixture was mixed with another batch (from 100 mg of 2-fluoro-3-nitropyridine) and partitioned between water and EtOAc. The organic layer was separated, dried over MgSO₄, filtered and concentrated to afford 2.03 g of intermediate 54 (91% yield) which was directly engaged in the next steps without any further treatment.

The intermediates in the Table below were prepared by using an analogous method starting from the respective starting materials.

Intermediate number Structure Mass (mg) Yield (%) Intermediate 60

2000 95 Intermediate 64

1340 Quant. Intermediate 68

1540 98 Intermediate 74

1440 97 Intermediate 78

936 99 Intermediate 82

944 Quant. Intermediate 86

1340 91 Intermediate 92

1090 89 Intermediate 122

737 53 Intermediate 130

816 96 Intermediate 134

1090 Quant. Intermediate 142

1070 78 Intermediate 150

560 45 Intermediate 170

1051 71 Intermediate 202

613 50 Intermediate 253

278 43 Intermediate 256

142 24 Intermediate 259

242 35 Intermediate 262

183 28 Intermediate 265

133 20 Intermediate 286

165 23 Intermediate 289

1260 (98% purity based on LC/MS) 94 Intermediate 309/ Intermediate 310

1549 79

Example A28 Preparation of Intermediate 100

A mixture of 2-chloro-3-nitropyridine (2.00 g, 12.61 mmol), 2-methoxyethanol (1.20 mL, 15.14 mmol) and Cs₂CO₃ (7.81 g, 23.97 mmol) in DMF (32 mL) was stirred all over the week end at rt. Additional 2-methoxyethanol (1.20 mL, 15.14 mmol) was added and the reaction mixture was heated at 80° C. overnight. The reaction mixture was poured into ice and extracted with EtOAc and Et₂O. The organic layer was washed with brine, dried over MgSO₄, filtered and evaporated to dryness to give 2.15 g of intermediate 100 (86% yield) used as it for the next step.

The intermediates in the Table below were prepared by using an analogous method starting from the respective starting materials.

Intermediate Mass Yield number Structure (mg) (%) Intermediate 118

629 15

Example A29 Preparation of Intermediate 138

In a Shlenck reactor, a solution of 6-chloro-2-methoxy-3-nitropyridine (1.00 g, 5.30 mmol), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (1.23 g, 5.83 mmol) and K₃PO₄ (3.38 g, 15.90 mmol) in 1,4-dioxane (44 mL) and distilled water (9 mL) was degassed under N₂. [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane (434.00 mg, 0.53 mmol) was added, the mixture was degassed again under N₂ and heated at 80° C. for 4 h. The mixture was extended with EtOAc and filtered on a pad of Celite®. The cake was washed with EtOAc and water. The layers were separated and the organic layer was dried over MgSO₄, filtered off and evaporated in vacuo to give a brown solid. The residue was purified by column chromatography on silica gel (irregular SiOH, 15-40 μm, 50 g, dry loading on Celite®, mobile phase: heptane/EtOAc, gradient: 95:5 to 60:40) to give 922 mg of intermediate 138 (74% yield, yellow solid).

The intermediates in the Table below were prepared by using an analogous method starting from the respective starting materials. The most relevant minor deviations to the referenced method are indicated as additional information in the column ‘Yield (%)’.

Intermediate number Structure Mass (mg) Yield (%) Intermediate 427

540 brown solid 83 procedure with T = 90° C. Intermediate 431

244 brown solid 99 procedure with T = 90° C.

Preparation of Intermediate 139

Pd/C (10 wt. %, 208.00 mg, 0.19 mmol) was added to a solution of intermediate 138 (922.00 mg, 3.90 mmol) in EtOH (20 mL) under N₂. The mixture was stirred at rt under an H₂ atmosphere (P_(atm)) overnight. The mixture was filtered on a pad of Celite® and the filtrate was evaporated in vacuo to give 800 mg of intermediate 139 (98% yield, white solid).

The intermediates in the Table below were prepared by using an analogous method starting from the respective starting materials. The most relevant minor deviations to the referenced method are indicated as additional information in the column ‘Yield (%)’.

Intermediate number Structure Mass (mg) Yield (%) Intermediate 159

230 orange oil 90 Intermediate 175

352 97 Intermediate 179

740 92 Intermediate 192

350 colourless oil 99 procedure with 4 bars pressure of H₂ Intermediate 215

300 11 Intermediate 219

35 18 Intermediate 226

774 (91% purity based on LC/MS) orange oil 88 Intermediate 234

968 pale brown oil 96 Intermediate 247

1330 pale pink solid 85 Intermediate 272

344 pale yellow cristals 97 procedure with (EtOAc/ Me—THF, 1:1, v/v) as solvent Intermediate 294

930 white solid 41 procedure with MeOH as solvent Intermediate 302

196 (93% purity based on LC/MS) brown oil 70 procedure with MeOH as solvent Intermediate 416

306 pink oil 73 Intermediate 420

770 orange oil 76 Intermediate 428

256 brown solid 99 Intermediate 432

212 black solid 86 Intermediate 436

374 (97% purity based on LC/MS) orange crystals Quant. Intermediate 442

318 pink solid —

Example A30 Preparation of Intermediate 146

Di-(1-adamantyl)-N-butylphosphine (143.00 mg, 0.40 mmol) and Pd(OAc)₂ (89.00 mg, 0.40 mmol) were added to a degassed (N₂) solution of 2,5-dichloro-3-nitropyridine (770.00 mg, 4.00 mmol), potassium cyclopropyltrifluoroborate (767.00 mg, 5.19 mmol) and Cs₂CO₃ (2.60 g, 7.98 mmol) in a mixture of 1,4-dioxane (18 mL) and distilled water (4 mL). The reaction mixture was then heated at 100° C. for 18 h, cooled to rt, poured onto water and extracted with DCM. The organic layer was decanted, dried over MgSO₄, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel (irregular SiOH, 24 g, mobile phase: heptane/DCM, gradient from 70:30 to 20:80). The pure fractions were collected and evaporated to dryness to give 190 mg of intermediate 146 (24% yield).

The intermediates in the Table below were prepared by using an analogous method starting from the respective starting materials.

Intermediate Mass Yield number Structure (mg) (%) Intermediate 206

566 55

Example A31 Preparation of Intermediate 154

In a Shlenck reactor, to a solution of 6-chloro-2-methoxy-3-nitropyridine (1.00 g, 5.30 mmol) in DMF (50 mL), N,N-dimethylacrylamide (820.00 μL, 7.96 mmol) and TEA (2.21 mL, 15.90 mmol) were added. The mixture was degassed under N₂ and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane (434.00 mg, 0.53 mmol) was added. The mixture was degassed again with N₂ and stirred at 100° C. overnight. The mixture was evaporated in vacuo. The residue was taken-up in EtOAc and brine and filtered on a pad of Celite®. The cake was washed with EtOAc. The layers were separated and the organic layer was washed with brine. The organic layer was dried over MgSO₄, filtered off and evaporated in vacuo to give a black solid. The residue (2.4 g) was purified by column chromatography on silica gel (irregular SiOH, 15-40 μm, 50 g, dry loading on Celite®, mobile phase: heptane/EtOAc/MeOH, gradient: from heptane 70%, EtOAc 27%, MeOH 3% to heptane 40%, EtOAc 54%, MeOH 6%). The pure fractions were combined and evaporated to dryness to give 566 mg of intermediate 154 (43% yield, orange solid).

The intermediates in the Table below were prepared by using an analogous method starting from the respective starting materials.

Intermediate number Structure Mass (mg) Yield (%) Intermediate 250

762 (91% purity based on LC/MS) dark grey powder 26 procedure with T = 120° C. Intermediate 299

600 (94% purity based on LC/MS) brown oil 47 procedure with T = 120° C.

Example A32 Preparation of Intermediate 174

NaH (60% dispersed in mineral oil) (111.00 mg, 2.78 mmol) was added slowly to dry 2-methoxyethanol (6 mL) at 0° C. (bubbling in the mixture). The mixture was stirred at 0° C. for 10 min and then, a solution of 2-chloro-3-nitro-6-(trifluoromethyl)pyridine (450.00 mg, 1.99 mmol) in 2-methoxyethanol (1 mL) was added dropwise (yellow coloration). The mixture was stirred at 0° C. for 1 h. The mixture was quenched with water and stirred for 1 h. EtOAc and brine were added and the layers were separated. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over MgSO₄, filtered off and evaporated in vacuo to give an orange oil. The residue was purified by column chromatography on silica gel (irregular SiOH, 15-40 μm, 24 g, mobile phase: heptane/EtOAc, gradient: from 95:5 to 70:30). The fractions containing the product were combined and concentrated in vacuo to give 410 mg of intermediate 174 (78% yield, colorless liquid).

The intermediates in the Table below were prepared by using an analogous method starting from the respective starting materials.

Intermediate number Structure Mass (mg) Yield (%) Intermediate 178

303 69 Intermediate 182

332 brown oil 22 with toluene as solvent Intermediate 186

4700 brown residue Quant with toluene as solvent Intermediate 197

1460 yellow oil 61 with toluene as solvent Intermediate 224

1630 orange liquid 67 with Me—THF as solvent Intermediate 233

1170 yellow oil 86

Example A33 Preparation of Intermediate 187

In a sealed tube, a mixture of intermediate 186 (800.00 mg, 3.69 mmol), dimethylphosphine oxide (341.00 mg, 4.06 mmol, purity 93%) and K₃PO₄ (862.00 mg, 4.06 mmol) in DMF (14.6 mL) was purged with N₂. Pd(OAc)₂ (83.00 mg, 0.37 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (214.00 mg, 0.37 mmol) were added. The mixture was purged with N₂ and stirred at 150° C. for 16 h. The mixture was evaporated in vacuo. The residue was diluted with DCM and water. The aqueous layer was extracted twice with DCM and the layers were separated. The combined organic layers were washed twice with brine, dried with MgSO₄, filtered and the solvent was removed under reduced pressure to give a brown oil. The residue was purified by column chromatography on silica gel (irregular SiOH 15-40 μm, 24 g, dry load on Celite®, mobile phase: DCM/MeOH (+10% aq. NH₃), gradient: from 100:0 to 80:20). The pure fractions were combined and evaporated under vacuum to give 330 mg of intermediate 187 (35% yield).

The intermediates in the Table below were prepared by using an analogous method starting from the respective starting materials.

Intermediate number Structure Mass (mg) Yield (%) Intermediate 198

439 (81% purity based on LC/MS) 27% (over 2 steps) Intermediate 306

1194 orange solid 60 Intermediate 328

405 pale red solid 65 Intermediate 424

130 (94% purity based on LC/MS) brown solid 35

Preparation of Intermediate 188

A mixture of intermediate 187 (310.00 mg, 1.20 mmol), Zn (785.00 mg, 12.00 mmol) and AcOH (0.69 mL, 12.00 mmol) in MeOH (5.70 mL) was stirred at rt for 16 h. The mixture was filtered on a pad of Celite® and the filtrate was diluted with DCM/MeOH (9/1) and water. The aqueous layer was saturated with K₂CO₃ powder and the layers were separated. The aqueous layer was extracted twice with DCM/MeOH (9/1). The combined organic layers were washed with brine, dried with MgSO₄, filtered and the solvent was removed under reduced pressure to give 260 mg of intermediate 188 (95% yield, brown oil).

The intermediates in the Table below were prepared by using an analogous method starting from the respective starting materials.

Intermediate number Structure Mass (mg) Yield (%) Intermediate 199

337 brown oil 86 Intermediate 290

1010 94

Example A34 Preparation of Intermediate 191

In a sealed glassware, a mixture of 6-chloro-2-methoxy-3-nitropyridine (0.70 g, 3.71 mmol), methyl propargyl ether (0.31 mL, 3.71 mmol) and Cs₂CO₃ (3.63 g, 11.10 mmo) in dry CH₃CN (7.40 mL) was purged with N₂. Then dichlorobis(acetonitrile)palladium (II) (48.00 mg, 0.19 mmol) and XPhos (177.00 mg, 0.37 mmol) were added. The mixture was purged with N₂ and stirred at 95° C. for 2 h. An extraction was performed with EtOAc and water and the layers were separated. The organic layer was dried over MgSO₄, filtered and the solvent was removed under reduced pressure to give a brown oil. The residue was purified by column chromatography on silica gel (irregular SiOH 15-40 μm, 40 g, dry loading on Celite®, mobile phase: heptane/EtOAc, gradient from 80:20 to 50:50). The pure fractions were combined and evaporated to dryness to give 440 mg of intermediate 191 (53% yield, pale brown solid).

Example A35 Preparation of Intermediate 210

A solution of 5-amino-6-bromo-3-pridinecarbonitrile (500.00 mg, 2.53 mmol) in THF (12 mL), was added to a premixed degassed solution of bis(tri-tert-butyl-phosphine)palladium (0) (129.00 mg, 0.25 mmol) in n-propyl bromide/THF (0.5 M, 10 mL) and the reaction mixture was stirred at rt for 3 h. The reaction mixture was poured onto a 10% aqueous solution of K₂CO₃ and EtOAc was added. The mixture was filtered through a pad of Celite® and the organic layer was decanted, washed with water, dried over MgSO₄, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel (irregular SiOH, 24 g, mobile phase: heptane/EtOAc, gradient from 90:10 to 70:30). The pure fractions were collected and evaporated to dryness to give 311 mg of intermediate 210 (76% yield).

The intermediates in the Table below were prepared by using an analogous method starting from the respective starting materials.

Intermediate Mass Yield number Structure (mg) (%) Intermediate 222

309 70

Example A36 Preparation of Intermediate 214

In a sealed vessel, 5-amino-6-bromo-3-pridinecarbonitrile (5.00 g, 25.25 mmol), cyclopropylacetylen (4.50 mL, 53.17 mmol) and TEA (10.80 mL, 75.75 mmol) were diluted in DMF (150 mL). The reaction mixture was degassed (N₂ bubbling) and PdCl₂(PPh₃)₂ (886.00 mg, 1.26 mmol) and CuI (967.00 mg, 5.05 mmol) were added. The reaction mixture was degassed with N₂ and stirred at rt for 2 h. The reaction mixture was quenched with water and extracted with a mixture of Et₂O and EtOAc. The organic layer was decanted, washed with brine, dried over MgSO₄, filtered over a pad of Celite® and evaporated to dryness. The residue was purified by column chromatography on silica gel (irregular SiOH, 80 g, mobile phase: heptane/EtOAc, gradient from 80:20 to 40:60). The pure fractions were collected and evaporated to dryness to give 2.81 g of intermediate 214 (61% yield).

The intermediates in the Table below were prepared by using an analogous method starting from the respective starting materials. The most relevant minor deviations to the referenced method are indicated as additional information in the column ‘Yield (%)’.

Intermediate number Structure Mass (mg) Yield (%) Intermediate 218

193 41 Intermediate 229

674 pale brown solid 73 procedure with T = 85° C. Intermediate 275

2970 (99% purity based on LC/MS) beige powder 498 (93% purity based on LC/MS) orange solid 64 11 procedure with T = 90° C.

Example A37 Preparation of Intermediate 225

In a Shlenck reactor, to a solution of intermediate 224 (1.60 g, 5.78 mmol) in a mixture of 1,4-dioxane (50 mL) and distilled water (12.5 mL), cyclopropylboronic acid (1.24 g, 14.40 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium (ii) dichloride, DCM complex (475.00 mg, 0.58 mmol) were added. The mixture was purged with N₂ and K₂CO₃ (2.39 g, 17.30 mmol) was added. The mixture was purged again with N₂ and stirred at 80° C. overnight. The mixture was combined with an other batch (from 20 mg of intermediate 224), filtered on a pad of Celite® and the cake was washed with EtOAc. The filtrate was evaporated in vacuo to give a black gum. The residue (3.1 g) was purified by column chromatography on silica gel (irregular SiOH, 15-40 μm, 80 g, dry loading on Celite®, mobile phase: heptane/EtOAc, gradient from 95:5 to 70:30). The pure fractions were combined and concentrated under vacuum to give 916 mg of intermediate 225 (66% yield, yellow liquid).

Example A38 Preparation of Intermediate 230

To a solution of intermediate 229 (527.00 mg, 3.06 mmol) in MeOH (11.8 mL), CoCl₂ (79.50 mg, 0.61 mmol) was added. The mixture was stirred at rt for 30 min then cooled down to 0° C. NaBH₄ (463.00 mg, 12.20 mmol) in DMF (6.6 mL) was slowly added and the mixture was stirred at 0° C. for 10 min then allowed to warm to rt and stirred for 30 min. The crude mixture was diluted with water and EtOAc. The aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO₄, filtered off and evaporated in vacuo to give a brown oil. The residue (629 mg) was purified by column chromatography on silica gel (Irregular SiOH, 15-40 μm, 24 g, dry loading on Celite®, mobile phase: heptane/(EtOAc/MeOH (90:10)), gradient from 90:10 to 50:50). The pure fractions were combined and evaporated to dryness to give 334 mg of intermediate 230 (62% yield, 78% purity based on LC/MS, brown oil) and used as it in the next step.

The intermediates in the Table below were prepared by using an analogous method starting from the respective starting materials.

Intermediate number Structure Mass (mg) Yield (%) Intermediate 276

3400 yellow oil 40 Procedure: cooled down to −50° C. before addition of NaBH₄ From intermediate 275

Example A39 Preparation of Intermediate 246

A mixture of intermediate 186 (2.00 g, 9.23 mmol), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (3.88 g, 18.50 mmol) and K₂CO₃ (1.63 g, 11.80 mmol) in a mixture of 1,4-dioxane (112 mL) and distilled water (28 mL) was purged with N₂. 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (300.90 mg, 461.60 μmol) was added and the mixture was purged with N₂ and was stirred at 90° C. for 15 h. The mixture was evaporated and extracted, then water and EtOAc were added. The layers were separated and the aqueous layer was extracted thrice with EtOAc. The organic layer was washed with brine, dried over MgSO₄ and concentrated. The residue was purified by column chromatography on silica gel (irregular SiOH 15-40 μm, 120 g, liquid loading in DCM, mobile phase: DCM). The fractions containing the product were combined and evaporated to dryness to give 1.85 g of intermediate 246 (76% yield, pale yellow solid).

Example A40 Preparation of Intermediate 271

In a microwave vial, a suspension of 3-amino-2-bromo-5-methylpyridine (500.00 mg, 2.67 mmol), N,N-dimethylacrylamide (689.00 μL, 6.68 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine) palladium (II) dichloride (94.60 mg, 0.13 mmol) and TEA (1.12 mL, 8.02 mmol) in DMF (12.5 mL) was purged with N₂ and was heated at 140° C. using one single mode microwave (Biotage Initiator) with a power output ranging from 0 to 400 W for 30 min [fixed hold time]. This reaction was performed in two batches from 500 mg of 3-amino-2-bromo-5-methylpyridine each. These two batches were combined and evaporated in vacuo. The residue was taken-up in EtOAc and water. The layers were separated and the aqueous layer was extracted twice with EtOAc and twice with DCM. The aqueous layer was saturated with K₂CO₃ and extracted twice with a mixture of DCM/MeOH (9:1). The combined organic layers were dried over MgSO₄, filtered off and evaporated in vacuo to give a brown solid. The residue (2.2 g) was purified by column chromatography on silica gel (irregular SiOH, 15-40 μm, 80 g, dry loading on Celite®, mobile phase: heptane/(EtOAc/MeOH (9:1)), gradient: from 70:30 to 15:85). The pure fractions were combined to give 815 mg of intermediate 271 (71% yield, yellow solid).

Example A41 Preparation of Intermediate 277

The reaction was performed in 2 batches.

In a sealed tube, a mixture of intermediate 276 (500.00 mg, 2.54 mmol), butyl vinyl ether (1.02 mL, 7.63 mmol) and NaHCO₃ (427.00 mg, 5.08 mmol) in MeOH (5 mL) was purged with N₂. Pd(OAc)₂ (11.40 mg, 50.80 μmol) and DPPP (31.50 mg, 76.20 μmol) was added. Then, the mixture was purged again with N₂ and heated at 130° C. for 1 h 30 min. This reaction was performed in 2 batches from 500 mg of intermediate 276 each. After cooling down to rt, the 2 batches were combined, cooled to 0° C. and quenched with a 3N aqueous solution of HCl. The solution was warmed to rt, stirred for 10 min, then neutralized with a 10% aqueous solution of K₂CO₃. EtOAc were added, the organic layer was separated and the aqueous layer was extracted thrice with EtOAc. The combined organic layers were dried over MgSO₄, filtered off and evaporated in vacuo to give pale brown oil which crystallized. The residue (1.14 g) was purified by column chromatography on silica gel (Irregular SiOH 15-40 μm, 50 g, liquid injection (DCM), mobile phase: heptane/EtOAc, gradient: from 90:10 to 70:30). The pure fractions were combined and evaporated to dryness to give 854 mg of intermediate 277 (82% yield, yellow solid).

Preparation of Intermediate 278

To a solution of methyl magnesium bromide (13.10 mL, 41.80 mmol) in Me-THF (50 mL) at −78° C. under N₂, intermediate 277 in Me-THF (35 mL) (854.00 mg, 4.18 mmol) was slowly added. The solution was allowed to warm to rt, stirred for 18 h then slowly quenched with water. EtOAc was added, the organic layer was separated, dried over MgSO₄, filtered off and evaporated in vacuo to give a yellow oil. The residue (968 mg) was purified by column chromatography on silica gel (Irregular SiOH 15-40 μm, 10 g, mobile phase: heptane/(EtOAc/MeOH (90:10)), gradient: from 90:10 to heptane 70:30). The fractions containing the product were combined and concentrated under vacuum to give a yellow oil. The residue (648 mg) was further purified by column chromatography on silica gel (Irregular SiOH 15-40 μm, 10 g, mobile phase: DCM/iPrOH, gradient: from 100:0 to 95:5). The pure fractions were combined and concentrated under vacuum to give 218 mg of intermediate 278 (23% yield, 97% purity based on NMR, pale yellow oil). This intermediate was used as it in the next step.

Example A42 Preparation of Intermediate 293

A flask was charged with methyl-6-chloro-5-nitronicotinate (2.00 g, 9.23 mmol), PdCl₂(PPh₃)₂ (324.00 mg, 461.70 μmol) and CuI (87.90 mg, 461.70 μmol). The system was evacuated and filled thrice with N2 before addition of TEA (44 mL) and DMF (88 mL) and the resulting solution was degassed with N₂ for 10 min. Then cyclopropylacetylene (1.56 mL, 18.49 mmol) was added and the reaction mixture was stirred at rt for 18 h. Then, the reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (Irregular SiOH 15-40 μm, 80 g, dry loading on Celite®, mobile phase: heptane/DCM, gradient from 50:50 to 0:100). The fractions containing the product were combined and concentrated under vacuum to give 1.3 g of intermediate 293 (58% yield, brown solid).

Example A43 Preparation of Intermediate 295

To a solution of intermediate 294 (500.00 mg, 2.27 mmol) in Me-THF (10 mL) and MeOH (10 mL), NaOH (1M in H₂O) (13.60 mL, 13.60 mmol) was added. The mixture was heated at 50° C. for 15 min. After cooling down to rt, the mixture was concentrated in vacuo. The residue was slowly acidified with a 1N aqueous solution of HCl (until pH=4). The resulting mixture was extracted with DCM/i-PrOH (3/1) (4 times). The combined organic layers were dried over Na₂SO₄ filtered and concentrated to give 322 mg of intermediate 295 (69% yield, 98% purity based on LC/MS, beige powder).

Preparation of Intermediate 296

To a solution of intermediate 295 (322.00 mg, 1.56 mmol) in DMF (15 mL), DIPEA (538.00 μL, 3.12 mmol), methylamine (3.12 mL, 6.25 mmol) and COMU(R) (1.67 g, 3.90 mmol) were added. The reaction mixture was stirred at rt for 24 h then concentrated to dryness. The residue was purified by column chromatography on silica gel (irregular SiOH 15-40 μm, 120 g, dry loading on Celite®, mobile phase: DCM/MeOH, gradient from 100:0 to 90:10). The fractions containing the product were combined and evaporated to dryness to give 282 mg of intermediate 296 (82% yield, white solid).

The intermediates in the Table below were prepared by using an analogous method starting from the respective starting materials.

Intermediate Yield number Structure Mass (mg) (%) Intermediate 317

275 pale brown solid 84 From 3-amino-2-methylpyridine- 5-carboxilic aid

Example A44 Preparation of Intermediate 305

To a solution of 5-chloro-2-methylpyridin-3-amine (2.00 g, 14.00 mmol) in CH₃CN (140 mL), NBS (2.62 g, 14.70 mmol) was added at 0° C. The solution was stirred 1 h at 0° C. The reaction mixture was diluted with water and EtOAc. The layers were separated. The aqueous layer was extracted twice with EtOAc, the combined organic layers were washed with brine, dried over MgSO₄, filtered and concentrated to give a brown solid. The residue was purified by column chromatography on silica gel (Irregular SiOH 15-40 μm, 80 g, dry loading on Celite®, mobile phase: DCM/MeOH, gradient from 100:0 to 95:5). The fractions containing the product were combined and concentrated under vacuum to give 2.88 g of intermediate 305 (93% yield, orange powder).

The intermediates in the Table below were prepared by using an analogous method starting from the respective starting materials.

Intermediate Mass Yield number Structure (mg) (%) Intermediate 327

632 brown solid 87 From intermediate 230

Example A45 Preparation of Intermediate 311 and Intermediate 312

A mixture of intermediates 309/310 (1.00 g, 4.94 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.03 g, 4.94 mmol) and K₃PO₄ (2.10 mg, 9.87 mmol) in 1,4-dioxane (17 mL) and F (9 mL) was degassed with N₂. [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane (404.00 mg, 0.49 mmol) was added and the reaction mixture was heated at 120° C. for 15 min using one single mode microwave (Biotage Initiator EXP 60) with a power output ranging from 0 to 400 W [fixed hold time]. The mixture was poured into ice and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO₄, filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (15-40 μm, 80 g, mobile phase: DCM/MeOH, gradient from 100:0 to 90:10). The pure fractions were mixed and the solvent was evaporated to give 0.338 g of intermediate 312 (28% yield) and 0.338 g of intermediate 311 (28% yield).

Preparation of Intermediate 313

Intermediate 311 (0.33 g, 1.35 mmol) with RaNi (0.055 g, 0.94 mmol) as a catalyst in MeOH (10 mL) was hydrogenated at rt overnight under 1.5 bar of H₂. The catalyst was filtered off and the filtrate was evaporated to give 0.298 g of intermediate 313 (100% yield).

Example A46 Preparation of Intermediate 337

To a solution of 6-chloro-2-methoxy-3-nitropyridine (100.00 mg, 0.53 mmol) in EtOH (2 mL), dimethylamine (40% in H₂O, 134 μL, 1.06 mmol) was added and the resulting mixture was stirred at rt for 1 h. The precipitate was collected by filtration, washed with EtOH and dried under high vacuum at 50° C. for 1 h to give 94 mg of intermediate 337 (90% yield, 47% purity based on LC/MS, off-white solid).

Example A47 Preparation of Intermediate 338

Intermediate 337 (94.00 mg, 0.48 mmol) and NCS (70.10 mg, 0.52 mmol) were added together in DMF (3.2 mL) and the resulting mixture was heated at 50° C. under N₂ for 30 min. The reaction was allowed to cool to rt, diluted with EtOAc and washed with saturated NaHCO₃ solution and brine. The organic layer was separated, dried over Na₂SO₄ and evaporated under reduced pressure to give 103 mg of intermediate 338 (93% yield, yellow solid).

Example A48 Preparation of Intermediate 415

To a solution of 2-methoxyethanol (266.76 μL, 3.37 mmol) in dry Me-THF (10 mL) under N₂, NaH (60% dispersed in mineral oil) (148.06 mg, 3.70 mmol) was added and the mixture was stirred at rt for 1 h. This suspension was added dropwise to a solution of 4,6-dichloro-2-methyl-5-nitropyrimidine (700.00 mg, 3.37 mmol) in dry Me-THF (25 mL) under N₂ at 0° C. The mixture was stirred at 0° C. for 2 h. The mixture was quenched with a sat. solution of NH₄Cl and extended with EtOAc. The layers were separated and the organic layer was washed with brine, dried over MgSO₄, filtered off and evaporated in vacuo to give an orange oil. The residue (1.1 g) was purified by column chromatography on silica gel (irregular SiOH, 15-40 μm, 50 g, dry loading on Celite®, mobile phase: heptane/EtOAc, gradient from 80:20 to 50:50). The fractions containing the product were combined and evaporated to dryness to give 570 mg of intermediate 415 which crystallized on standing (68% yield, yellow oil).

The intermediates in the Table below were prepared by using an analogous method starting from the respective starting materials. The most relevant minor deviations to the referenced method are indicated as additional information in the column ‘Yield (%)’.

Intermediate Mass Yield number Structure (mg) (%) Intermediate 419

1.34 yellow oil 68 From 4,6-dichloro-2- methyl-5-nitropyrimidine and tetrahydrofurfuryl alcohol Intermediate 423

310 white solid 25 procedure with DMF as solvent From 5-amino-2,4- dichloropyrimidine and 2-methoxyethanol Intermediate 435

425 orange oil 65 From 4,6-dichloro-2- methyl-5-nitropyrimidine and 3-hydroxymethyl- 3-methyloxetane Intermediate 441

360 beige solid 55 From 4,6-dichloro-2-methyl- 5-nitropyrimidine and 2- hydroxy-N,N- dimethylacetamide

Example A49 Preparation of Intermediate 445

LiHMDS 1.5M in THF (2.6 mL; 3.84 mmol) was added dropwise at 5° C. to a solution of 4-methyl-3-(hydroxymethyl)morpholine (420 mg; 3.20 mmol) in Me-THF (12 mL). After 30 min, 2-fluoro-5-methyl-3-nitropyridine (500 mg; 3.20 mmol) was quickly added and the reaction mixture was allowed to warm to room temperature and stirred at rt overnight. LiHMDS 1.5M in THF (854 μL; 1.28 mmol) was added at 0° C. and the mixture was stirred at rt for 5 h. The reaction mixture was poured onto iced water, a 10% aqueous solution of K₂CO₃ and extracted with EtOAc. The organic layer was decanted, washed with water, dried over MgSO₄, filtered and evaporated to give 733 mg of crude. The crude was purified by chromatography over silica gel (SiOH, GraceResolv®, 12 g, Mobile phase DCM/MeOH/NH₄OH, Gradient from: 99% DCM, 1% MeOH, 0.1% NH₄OH to 97% DCM, 3% MeOH, 0.3% NH₄OH). The pure fractions were collected and the solvent was evaporated to give 544 mg of intermediate 445 (64% yield, yellow solid).

Chiral separation of intermediate 445 was performed via chiral SFC (Stationary phase: CHIRALPAK AD-H 5 μm 250×20 mm, Mobile phase: 70% CO₂, 30% MeOH). The pure fractions were collected and the solvent was evaporated to give 254 mg of intermediate 446 (30% yield, yellow solid) and 262 mg of intermediate 447 (31% yield, yellow solid).

Intermediate Mass Yield number Structure (mg) (%) Intermediate 446

254 30 procedure with T = rt o/n From 4-methyl-3- (hydroxymethyl)morpholine and 2-fluoro-5-methyl-3- nitropyridine Intermediate 447

262 31 procedure with T = rt o/n From 4-methyl-3- (hydroxymethyl)morpholine and 2-fluoro-5-methyl-3- nitropyridine

The intermediates in the Table below were prepared by using an analogous method starting from the respective starting materials. The most relevant minor deviations to the referenced method are indicated as additional information in the column ‘Yield (%)’. Chiral SFC could optionally be used for the separation of diastereoisomers, with minor modifications to either the stationary phase and/or the mobile phase that would be readily achieved by one skilled in the art.

Inter- mediate Mass Yield number Structure (mg) (%) Inter- mediate 541

302 75 CIS mixture (RS and SR) From 2-Fluoro-5-methyl-3-nitropyridine and cis-1-boc-3-fluoro-4- hydroxypiperidine Inter- mediate 459

2.1 g 84 From 2-fluoro-5-methyl-3-nitropyridine and (r,s)-tert-butyl 2- (hydroxymethyl)morpholine-4- carboxylate Inter- mediate 453

193 contains 5-10% of interme- diate 454 28 TRANS A (SS or RR) From 2-fluoro-5-methyl-3- nitropyridine and intermediate 452 Inter- mediate 454

191 28 TRANS B (RR or SS) From 2-fluoro-5-methyl-3- nitropyridine and Intermediate 452 Inter- mediate 498

450 40 From 2,6-dichloro-3-methyl- 5-nitro-pyridine and isopropyl alcohol Inter- mediate 556

104 58 From 2-fluoro-5-methyl-3- nitropyridine and intermediate 555 Inter- mediate 563

450 76 TRANS mixture (RR and SS) From 2-fluoro-5-methyl-3-nitropyridine and trans-1-boc-3-fluoro-4-hydroxypiperidine

Example A50 Preparation of Intermediate 448

A mixture of intermediate 446 (250 mg; 0.94 mmol), NH₄Cl (200 mg; 3.74 mmol) and Iron Powder (261 mg; 4.68 mmol) in EtOH (3.5 mL) and water, distilled (1.5 mL) was heated at 75° C. for 4 h. The reaction mixture was cooled to room temperature, poured onto a mixture of 10% aqueous K₂CO₃ and DCM, then filtered through a pad of Celite®. The organic layer was decanted, dried over MgSO₄, filtered and the solvent was evaporated to give 204 mg of crude (orange oil). The crude was purified by chromatography over silica gel (SiOH, Biotage, SNAP 10 g, Mobile phase DCM/MeOH/NH₄OH, Gradient from 98% DCM, 2% MeOH, 0.2% NH₄OH to 95% DCM, 5% MeOH, 0.5% NH₄OH). The pure fractions were collected and the solvent was evaporated to give 160 mg of intermediate 448 (72% yield, yellow oil).

The intermediates in the Table below were prepared by using an analogous method starting from the respective starting materials. The most relevant minor deviations to the referenced method are indicated as additional information in the column ‘Yield (%)’. Chiral SFC could optionally be used for the separation of diastereoisomers, with the appropriate choice of either the stationary phase and/or the mobile phase that would be readily achieved by one skilled in the art.

Inter- mediate Mass Yield number Structure (mg) (%) Inter- mediate 450

169 74 From intermediate 447 Inter- mediate 544

73 68 procedure with T = 70° C. o/n CIS mixture (RS and SR) From intermediate 543 Inter- mediate 476

349 97 procedure with T = 65° C. 1 h From intermediate 475 Inter- mediate 464

318 80 From intermediate 462 Inter- mediate 466

283 71 From intermediate 463 Inter- mediate 455

134 79 procedure with T = 75° C. 3 h TRANS A (SS or RR) From intermediate 453 Inter- mediate 457

109 65 procedure with T = 75° C. 3 h TRANS B (RR or SS) From intermediate 454 Inter- mediate 469

181 66 procedure with T = 80° C. 1 h From intermediate 468 Inter- mediate 472

91 30 procedure with T = 80° C. 2 h From intermediate 471 Inter- mediate 557

31 34 procedure with T = 70° C. 30 mn From intermediate 556 Inter- mediate 566

250 97 procedure with T = 70° C. 1 h TRANS mixture (RR and SS) From intermediate 565 Inter- mediate 559

159 Quant. procedure with T = 80° C. 1 h 30 From intermediate 488 Inter- mediate 585

174 65% Procedure with T = 80° C. 1 hr From intermediate 584

Example A51 Preparation of Intermediate 547

Intermediate 484 (0.160 g; 0.60 mmol) was hydrogenated at atmospheric pressure and at rt in MeOH (4.00 mL) and EtOAc (2.00 mL) with Pd/C (10% w/w, 0.060 g; 0.06 mmol) as a catalyst. After 2 hours the catalyst was filtered over Celite® and the solvent was evaporated until dryness to give: 160 mg of intermediate 547 (100% yield)

The intermediates in the Table below were prepared by using an analogous method starting from the respective starting materials. The most relevant minor deviations to the referenced method are indicated as additional information in the column ‘Yield (%)’.

Inter- mediate Mass number Structure (mg) Yield (%) Inter- mediate 501

270 91 From intermediate 500 Inter- mediate 496

837 100 Procedure with 2 bars pressure of H₂, rt, o/n From intermediate 495 Inter- mediate 550

470 99 Procedure with atmospheric pressure H₂ 2 h From intermediate 485 Inter- mediate 491

590 100 Procedure with atmospheric pressure H₂ 3 h From intermediate 489 Inter- mediate 493

403 93 Procedure with atmospheric pressure H₂ 12 h From intermediate 490 Inter- mediate 507

388 96 Procedure with atmospheric pressure H₂ 7 h From intermediate 482

Example A52 Preparation of Intermediate 542

In a round bottom flask containing intermediate 541 and dioxane (5 mL) was added HCl (6.3 mL) and the reaction was left stirring at room temperature overnight.

The crude was concentrated in vacuo before being quenched with a saturated solution of NaHCO₃ and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give a crude that was purified by flash chromatography eluting with [DCM:MeOH 75:25] to give intermediate 542 (187 mg; 87% yield)

The intermediates in the Table below were prepared by using an analogous method starting from the respective starting materials. The most relevant minor deviations to the referenced method are indicated as additional information in the column ‘Yield (%)’.

Intermediate Mass Yield number Structure (mg) (%) Intermediate 564

320 99 TRANS mixture (RR and SS) From intermediate 563 Intermediate 487

500 83 From intermediate 486

Example A53 Preparation of Intermediate 460

TFA (4.2 mL; 54.33 mmol) was added dropwise at 5° C. to a suspension of intermediate 459 (1.92 g; 5.43 mmol) in DCM (38 mL) and the reaction mixture was stirred at rt for 2 h. The reaction mixture was diluted with ice-water, a 10% aqueous solution of K₂CO₃ and DCM. The mixture was extracted with DCM (5×). The layers were separated and the organic layer was dried over MgSO₄, filtered and the solvent was evaporated. The residue was combined with that from a parallel experiment and the solvent was evaporated to give in total 1.48 g of intermediate 460 as a yellow oil. The product was used without purificaton for subsequent reactions.

Example A54 Preparation of Intermediate 452

Formaldehyde (10 mL; 134.21 mmol) was added to a mixture of trans-4-fluoro-3-hydroxypyrrolidine hydrochloride (950 mg; 6.71 mmol) and AcOH (768 μL; 13.42 mmol) in MeOH (54 mL) at rt. The reaction mixture was stirred at rt for 30 min, then sodium triacetoxyborohydride (3.56 g; 16.78 mmol) was added and the reaction mixture was stirred at rt for 3 h. The mixture was basified with a saturated aqueous NaHCO₃ solution at 5° C. and the solvent was evaporated. The mixture was diluted with EtOAc and washed with saturated aqueous NaHCO₃ solution, then extracted with EtOAc (3×). Then, the aqueous layer was extracted with DCM (3×). The organic layer was combined, dried over MgSO₄, filtered and the solvent was evaporated to give 445 mg of intermediate 452 as a pale brown volatile oil.

The intermediates in the Table below were prepared by using an analogous method starting from the respective starting materials. The most relevant minor deviations to the referenced method are indicated as additional information in the column ‘Yield (%)’.

Intermediate Mass number Structure (mg) Yield (%) Intermediate 462

450 29 SFC separation of racemate into enantiomers From intermediate 460 Intermediate 463

450 29 SFC separation of racemate into enantiomers From intermediate 460

Example A55 Preparation of Intermediate 543

To a solution of intermediate 542 in MeOH (8 mL, 1.528 mmol) was added formaldehyde (124 μL) and then Formic acid (288 μL, 0.00764 mmol). The reaction mixture was stirred at room temperature for 1 hour. Then, sodium triacetoxyborohydride (202 mg, 0.955 mmol) was added and the stirring was continued for 1 hour. Then, the reaction mixture was carefully quenched by addition of NaHCO₃ sat. (2 mL) and extracted with ethyl acetate.

The organic layer was evaporated to dryness and was purified by silica gel column chromnatography [DCM:MeOH 9:1 30%] to afford intermediate 543 (121 mg; 59% yield).

The intermediates in the Table below were prepared by using an analogous method starting from the respective starting materials. The most relevant minor deviations to the referenced method are indicated as additional information in the column ‘Yield (%)’.

Intermediate Mass Yield number Structure (mg) (%) Intermediate 565 Trans

290 86 TRANS mixture (RR and SS) From intermediate 564

Example A56 Preparation of Intermediate 488

In a sealed tube, a mixture of intermediate 487 (0.500 g; 1.99 mmol); ethoxycyclopropoxy)trimethyl silane (0.41 mL; 2.04 mmol) and NaBH₃CN (0.175 g; 2.79 mmol) in AcOH (5.50 mL) and MeOH (0.16 mL; 2.80 mmol) was stirred at 60° C. overnight. The reaction was cooled down to room temperature. Water was added and this mixture was extracted twice with EtOAc. The organic layer was decanted and evaporated until dryness to give: 0.455 g of crude intermediate 488. This crude was purified by preparative LC (Irregular SiOH 15-40 μm 40 g GraceResolv®, mobile phase gradient from: 99% DCM, 1% MeOH, 0.1% NH₄OH to 94% DCM, 6% MeOH, 0.6% NH₄OH). The pure fractions were collected and the solvent was evaporated until dryness to give a combined yield of 295 mg (51%) of intermediate 488

Example A57 Preparation of Intermediate 471

In a sealed tube, a mixture of 2-hydroxy-5-methyl-3-nitropyridine (463 mg; 3.00 mmol), 3-bromomethyl-3-methyloxetane (991 mg; 6.01 mmol) and K₂CO₃ (1.25 g; 9.01 mmol) in DMF (6 mL) was stirred at 60° C. for 2 h. The reaction mixture was cooled down to room temperature. The insoluble material was filtered off and the filtrate was concentrated. The residue poured onto a mixture of water and brine, then extracted with EtOAc. The organic layer was decanted, washed with brine, dried over MgSO₄, filtered and the solvent was evaporated to give 750 mg of crude product as a yellow oil. The crude was purified by chromatography over silica gel (irregular SiOH, 24 g; gradient: from 100% DCM to 98% DCM, 2% MeOH). The pure fractions were collected and the solvent was evaporated to give intermediate 471 in 2 fractions: 287 mg of a yellow oil (40% yield) and 365 mg of a yellow solid (51% yield).

Example A58 Preparation of Intermediate 474

Tetrakis(triphenylphosphine)palladium(0) (167 mg; 0.145 mmol) was added to a stirred suspension of 2-chloro-3-nitro-5-picoline (500 mg; 2.897 mmol) and vinylboronic acid pinacol ester (516 μL; 3.042 mmol) in 1,4-dioxane (15 mL) and Na₂CO₃ 2M (4 mL). The mixture was stirred at 100° C. for 4 hours. Then, water was added and the mixture was extracted with AcOEt. The organic layer was decanted, dried over MgSO₄, filtered and evaporated to dryness. The crude product was purified by chromatography over silica gel (irregular SiOH, 12 g; Mobile phase: gradient from 10% EtOAc, 90% heptane to 20% EtOAc, 80% heptane). The desired fractions were collected and evaporated to dryness yielding 403 mg of intermediate 474 (85% yield).

Preparation of Intermediate 475

In a sealed tube, a mixture of intermediate 474 (403 mg; 2.455 mmol), 3-fluoroazetidine hydrochloride (821 mg; 7.365 mmol) and Et₃N (1.36 mL; 9.819 mmol) in EtOH (10 mL) was refluxed for 1 hour. The reaction mixture was evaporated to dryness and purified by chromatography over silica gel (irregular SiOH, 24 g; mobile phase: gradient from 3% MeOH, 97% DCM to 5% MeOH, 95% DCM). The pure fractions were collected and evaporated to dryness yielding 410 mg of intermediate 475 (70% yield).

The intermediate in the Table below was prepared by using an analogous method starting from the respective starting materials. The most relevant minor deviations to the referenced method are indicated as additional information in the column ‘Yield (%)’.

Intermediate Mass number Structure (mg) Yield (%) Intermediate 584

298 72 Procedure with MeOH; no Et₃N; refluxed 18 hrs From intermediate 474 and cyclopropylamine

Example A59 Preparation of Intermediate 478

Lithium aluminium hydride in solution 1M THF (5.4 mL; 5.40 mmol) was added dropwise to a solution of 4-amino-5-methylpyridine-2-carboxylate methyl ester HCl salt (300 mg; 1.48 mmol) in Me-THF (4.2 mL) at 0° C. and under N₂ flow. The reaction mixture was stirred at rt overnight. The mixture was cooled to 0° C. and ice-water then cooled solution of NaOH 3N and ice-water were successively added dropwise at 0° C. The material was combined with that from a parallel reaction for the treatment. EtOAc was added and the reaction mixture was filtered on a short pad of Celite®. The Celite® was washed with AcOEt and water was added. The filtrate was extracted with EtOAc (3×). The organic layer was washed with water then brine, dried over MgSO₄, filtered and the solvent was evaporated to give 80 mg of intermediate 478 as an orange oil.

NaCl solid was added to the aqueous layer and the product was extracted with EtOAc (3×). As the product was found to persist in the aqueous layer, this was evaporated to dryness and the residue was taken up with 50 mL of solution of DCM/MeOH (90/10). The mixture was stirred at rt for 5 min and then filtered. The cake was treated a further 2 times in the same fashion before combining all the organic fractions, drying over MgSO₄, filtering and evaporating the solvent in vacuo. The residue was combined with 80 mg initially isolated to give after evaporation 391 mg of crude intermediate 478 as a brown solid. The crude was purified by chromatography over silica gel (SiO2, Grace, 12 g, eluent: from 96% DCM, 4% MeOH, 0.4% NH₄OH to 90% DCM, 10% MeOH, 1% NH₄OH). The pure fractions were collected and the solvent was evaporated to give 69 mg of intermediate 478 as a white solid (28% yield).

Example A60 Preparation of Intermediate 480

2-methoxy-3-methyl-5-nitropyridine (4.30 g; 25.57 mmol) and tert-butyl chloroacetate (4.50 mL; 31.37 mmol) in THF (60 mL) was stirred and cooled at −20° C. Then potassium tert-butoxide (6.80 g; 60.60 mmol) was added portionwise to this mixture (temperature keep below −14° C.). After complete addition, this reaction was stirred at rt for 1 h. Water and an aqueous solution of HCl 3N were added and this mixture was extracted twice with EtOAc. The organic layer was decanted and the solvent was evaporated until dryness to give 7.35 g of intermediate 480 (100% yield).

Preparation of Intermediate 481

At rt, TFA (3.50 mL; 45.74 mmol) was added slowly to a solution of intermediate 480 (1.00 g; 3.54 mmol) in DCM (3.00 mL). This reaction was stirred at 100° C. for 1 h. The solvent was evaporated until dryness to give 863 mg of intermediate 481 (100% yield)

Preparation of Intermediate 482

A mixture of intermediate 481 (0.860 g; 3.80 mmol) and K₂CO₃ powder (0.350 g; 2.53 mmol) in DMF (2.90 mL) was stirred at 90° C. for 2 h, before being allowed to cool down to rt. The reaction was poured onto a mixture of ice and water and this mixture was stirred for 15 minutes. The precipitate was filtered and dried until dryness to give: 485 mg of intermediate 482 (70% yield)

Preparation of Intermediate 483

Intermediate 482 (100 mg, 0.55 mmol) in CH₃CN (7.20 mL) was treated with sodium iodide (123 mg, 0.82 mmol) and chlorotrimethyl silane (0.14 mL, 1.10 mmol). The reaction was stirred at 80° C. overnight. Water was added and this mixture was extracted twice with EtOAc. The organic layer was decanted and the solvent was evaporated until dryness. The crude was taken up into diethyl ether, triturated and filtered. This precipitate was dried until dryness to give: 70 mg of intermediate 483 (76% yield), which was used as is for the next step.

Preparation of Intermediate 484

A mixture of intermediate 483 (0.241 g; 1.43 mmol), 4-hydroxy-1-methylpiperidine (0.198 g; 1.72 mmol) in toluene (4.10 mL) and CMPB (0.66 mL; 2.52 mmol) was stirred in a sealed tube at 110° C. using one single mode microwave (Anton Parr monowave 300) with a power output ranging from 0 to 850 W for 15 min. [fixed hold time]. Water was added and this mixture was extracted twice with EtOAc. The crude was purified by preparative LC (Irregular SiOH 40 μm 24 g GraceResolv®, mobile phase Gradient from: 98% DCM, 2% MeOH, 0.2% NH₄OH to 90% DCM, 10% MeOH, 1% NH₄OH). The pure fractions were collected and the solvent was evaporated until dryness to give: 125 mg of intermediate 484 (33% yield).

(The product was combined with another batch from a parallel experiment and used as is in subsequent reactions.)

The intermediates in the Table below were prepared by using an analogous method starting from the respective starting materials. The most relevant minor deviations to the referenced method are indicated as additional information in the column ‘Yield (%)’.

Intermediate Mass number Structure (mg) Yield (%) Intermediate 485

540 60 Procedure at 110° C., 15 mn, μw From intermediate 483 and tetrahydro- 4-pyranol Intermediate 468

241 37 Procedure at 110° C., 20 mn, μw From 2-hydroxy-5-methyl-3- nitropyridine and 4-hydroxy-1- methylpiperidine Intermediate 486

785 37 Procedure at 110° C., 15 mn, μw From intermediate 483 and 1-BOC-4-hydroxy-piperidine Intermediate 489

630 76 From 3-methyl-3- oxetanemethanol and 483 Intermediate 490

495 82 From 483 and 3-oxetanemethanol

Example A61 Preparation of Intermediate 513

At rt, NaH (60% dispersion in mineral oil) (264 mg; 6.60 mmol) was added portionwise to a mixture of intermediate 480 (1.20 g; 4.25 mmol) in DMF (30.00 mL). Then 2-iodopropane (0.55 mL; 5.50 mmol) was added to this mixture. The reaction was stirred at rt overnight. Water was added and this mixture was extracted twice with EtOAc. The organic layer was decanted and the solvent was evaporated until dryness. The crude was purified by preparative LC (Irregular SiOH, 15-40 μm, 80 g GraceResolv®, Mobile phase Heptane/EtOAc, Gradient from: 90:10 to 60:40). The pure fractions were collected and the solvent was evaporated until dryness to give 0.984 g of intermediate 513 (71% yield).

Preparation of Intermediate 514

TFA (2.40 mL; 31.36 mmol) was added to a solution of intermediate 513 (0.980 g; 3.02 mmol) in DCM (3.50 mL). This reaction was stirred at 110° C. for 2 h. The solvent was evaporated until dryness to give 984 mg of intermediate 514 (100% yield).

Preparation of Intermediate 515

A mixture of intermediate 514 (0.98 g; 3.67 mmol) in DMF (40.00 mL) and K₂CO₃ (1.00 g; 7.24 mmol) was stirred at 90° C. for 3 h. The reaction was cooled down to room temperature. This mixture was poured onto a mixture of ice/water, an aqueous solution of HCl 3N was added. This mixture was extracted twice with EtOAc. The organic layer was decanted and the solvent was evaporated until dryness. This crude was purified by preparative LC (Irregular SiOH 40 μm, 80 g, GraceResolv®, Mobile phase Heptane/EtOAc, Gradient from: 90:10 to 70:30). The pure fractions were evaporated until dryness to give 0.476 g of intermediate 515 (58% yield).

Preparation of Intermediate 513

Intermediate 515 (0.47 g; 2.11 mmol) was hydrogenated at rt in EtOAc (4.00 mL) and MeOH (6.00 mL) with Pd/C (10% wt., 0.12 g; 0.11 mmol) as a catalyst at atmospheric pressure of H₂. After overnight the catalyst was filtered over Celite® and the solvent was evaporated until dryness to give 0.402 g of intermediate 516 (98% yield).

Example A62 Preparation of Intermediate 495

A mixture of 2-bromo-5-methyl-3-nitropyridine (1 g; 4.61 mmol), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (2.42 g; 6.91 mmol), tetrakis(triphenylphosphine)palladium(0) (160 mg; 0.138 mmol) in 1,4-dioxane (19 mL) and 2M Na₂CO₃ (6.3 mL; 12.6 mmol) under N₂ atmosphere was stirred and heated at 100° C. for 1 h. Then, water was added and the mixture was extracted with DCM. The organic layer was separated, dried (MgSO₄) filtered and concentrated. The residue was purified by flash chromatography over silica gel (eluent: gradient from DCM to DCM/MeOH: 100/0 to 95/5). The desired fractions were collected and concentrated till dryness, yielding: 0.988 g of intermediate 495 (97% yield).

Example A63 Preparation of Intermediate 499

In a sealed tube, intermediate 498 (1.5 g; 0.065 mol), potassium vinyltrifluoroborate (1.22 g; 0.009 mol), PdCl₂dppf (106.4 mg; 0.13 mmol) and Et₃N (0.904 mL; 0.0065 mol) in n-propanol (15.8 mL) under a N₂ flow were heated at 120° C. for 3 h. The mixture was partitioned between water and EtOAc. The organic layer was dried over MgSO₄, filtered and concentrated in vacuo. The residue was purified by chromatography over silica gel (15-40 μm, 40 g, eluent: heptane/EtOAc: 95/5 to 90/10). The pure fractions were mixed and the solvent was evaporated yielding 0.317 g (22%) of the pure intermediate 499 as a yellow oil, and an impure second fraction which was purified again by chromatography over silica gel (15-40 μm, 40 g, eluent: heptane/EtOAc: 95/5). The pure fractions were mixed and evaporated to give a second pure batch of intermediate 499 (240 mg; 13% yield). Combined yield 35%.

Preparation of Intermediate 500

In a sealed tube, a mixture of intermediate 499 (0.317 g; 1.43 mmol), Et₃N (1.021 mL; 7.13 mmol) and 3-fluoroazetidine hydrochloride (535 mg; 7.13 mmol) in ethanol (10.69 mL) were stirred at 100° C. for 4 h. The reaction mixture was cooled down to room temperature and partitioned between DCM and a saturated solution of NaHCO₃. The organic layer dried over MgSO₄, filtered and concentrated to afford intermediate 500 (0.431 mg) which were directly engaged in subsequent reactions without any further treatement.

Example A64 Preparation of Intermediate 503

To a solution of 2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.542 g; 6.912 mmol) in water (4.00 mL) and 1,4 dioxane (20 mL) was added K₃PO₄ (4.40 g; 20.74 mmol), tetrakis(triphenylphosphine)palladium(0) (Pd(PPh₃)₄) (798.70 mg, 0.69 mmol), 5-bromo-2-methyl-3-nitropyridine (1.50 g; 6.91 mmol) under N₂. The mixture was stirred at 80° C. overnight under N₂. The mixture was then poured into water (20 mL) and extracted three times with EtOAc (30 mL). The organic layer was washed with water (15 mL) and then brine (15 mL), dried over Na₂SO₄, filtered and the solvent was evaporated under vacuum. The residue was purified by flash column chromatography over silica gel (Mobile phase: petroleum ether/EtOAc Gradient from: 100:0 to 31:69 then EtOAc/MeOH Gradient from 100:0 to 90:10). The desired fractions were collected and the solvent was concentrated to dryness under vacuum to give 900 mg (56% yield) of intermediate 503 as a yellow oil

Preparation of Intermediate 504

A mixture of intermediate 503 (0.90 g; 3.86 mmol) in MeOH (30 mL) was hydrogenated at rt (20 Psi) with Pd(OH)₂/C (20 wt. %, 0.10 g) as a catalyst. After uptake of H₂ (4 equivalent), the mixture was stirred overnight at 30° C.

The catalyst was filtered off through Celite® and the filtrate was evaporated to give 650 mg of intermediate 504 (81% yield) as a black oil.

Example A65 Preparation of Intermediate 510

In a sealed tube, 3-amino-2-bromo-5-methylpyridine (2 g; 10.7 mmol), methyl propargyl ether (2.71 mL; 32.4 mmol) and Et₃N (4.59 mL; 32.1 mmol) were diluted in DMF (64 mL). The reaction mixture was degassed (N₂ bubbling) and PdCl₂(PPh₃)₂ (375 mg; 0.535 mmol) and CuI (409 mg; 2.14 mmol) were added. The reaction mixture was stirred at 50° C. overnight. The reaction mixture was poured onto water and extracted with EtOAc/Et₂O. The organic layer was decanted, washed with brine, dried over MgSO₄, filtered and evaporated to dryness. The residue was purified by chromatography over silica gel (irregular SiOH, 90 g; mobile phase: gradient from 20% EtoAc, 80% heptane to 100% EtOAc, 0% heptane). The pure fractions were collected and evaporated to dryness. yielding: 1.45 g intermediate 510 (77% yield).

Preparation of Intermediate 511

A solution of intermediate 510 (1.45 g, 8.228 mmol) in MeOH was hydrogenated under 2 bars of H₂ at rt in presence of Pd/C (10%) (242.85 mg, 0.228 mmol) overnight. The mixture was filtered over Celite®. To the filtrate was added again MeOH. The mixture was hydrogenated under 2 bars of H₂ at rt overnight. The mixture was filtered over Celite®. The filtrate was evaporated, yielding: 1.325 g of intermediate 511 (89% yield).

Example A66 Preparation of Intermediate 521

A mixture of 2-bromo-5-chloro-3-nitropyridine (2.8 g; 11.79 mmol) and copper(I) cyanide (1.40 g, 15.63 mmol) in DMF (30 mL) was stirred at 110° C. for 1.5 h. The mixture was concentrated. The residue was diluted with water (60 mL), extracted three times with EtOAc (50 mL). The organic phase was washed with brine, dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography (elution: DCM/Petroleum ether 1/1). The desired fractions were collected and concentrated to give 1.10 g of intermediate 521 (51% yield) as a yellow solid.

Preparation of Intermediate 522

A mixture of intermediate 521 (1.01 g; 5.50 mmol) in H₂SO₄ cc (5 mL) was stirred at 120° C. for 90 min. The mixture was cooled to rt. A solution of NaNO₂ (996.2 mg; 14.44 mmol) in water (1.8 mL) was added dropwise at −5° C. for 15 min. The resulting mixture was warmed to rt and stirred for 30 min. Then the mixture was stirred at 80° C. for 60 min. The mixture was cooled to rt and poured into ice/water, extracted three times with EtOAc (3*15 mL). The organic phase was dried over Na₂SO₄, filtered and concentrated to give 1.11 g of intermediate 522 (100% yield) as a yellow solid

Preparation of Intermediate 523

Intermediate 522 (1.10 g, 5.43 mmol) was dissolved in DMF (25.0 mL). HATU (3.10 g, 8.15 mmol) and DIPEA (3.51 g, 27.15 mmol) were added. The mixture was stirred at rt for 5 min. Methylamine hydrochloride (0.92 g; 13.58 mmol) was added. The reaction was stirred at rt overnight. The mixture was diluted with water (20 mL), extracted three times with EtOAc (20 mL). The organic phase was washed with brine, dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography (Mobile phase:Petroleum ether/EtOAc 1:1). The desired fractions were collected and concentrated to give 670 mg of intermediate 523 (57% yield) as a solid.

Preparation of Intermediate 524

Intermediate 523 (0.67 g, 3.11 mmol) was dissolved in MeOH (24.0 mL) and water (6.00 mL). Iron (0.87 g; 15.54 mmol) and NH₄Cl powder (1.66 g; 31.08 mmol) were added. This reaction was refluxed for 2 h. The mixture was cooled to rt and filtered. The filtrate was diluted with DCM (100 mL), washed with brine. The organic layer was dried over Na₂SO₄, filtered and concentrated to give 0.428 g intermediate 524 (74% yield) as a solid.

Example A67 Preparation of Intermediate 527

A mixture of 2-bromo-5-methylpyridin-4-amine (2.70 g; 14.44 mmol), Et₃N (4.38 g; 43.30 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex (1.18 g; 1.44 mmol) in MeOH (100 mL) was stirred at 80° C. under an atmosphere of carbon monoxide (0.5 MPa) overnight. The mixture was filtered through Celite®, and the solvent was evaporated in vacuum to give 2.4 g of crude material. The crude was purified by column chromatography over silica gel (Mobiled phase: Ethyl acetate/MeOH 5:1). The desired fractions were evaporated in vacuum to give 1.53 g of intermediate 527 (64% yield) as a brown solid.

Preparation of Intermediate 528

A solution of intermediate 527 (1.53 g; 9.21 mmol) and methylamine 2M in THF (51.00 mL; 102 mmol) in MeOH (50.00 mL) was stirred at 60° C. overnight. The mixture was evaporated in vacuum to give 1.50 g of crude material. The crude was purified by column chromatography over silica gel (Mobile phase: EtOAc/MeOH 10:1). The desired fractions were evaporated in vacuum to give 1.17 g of intermediate 528 (77% yield) as a brown solid.

Example A68 Preparation of Intermediate 531

A solution 2-bromo-5-methylpyridin-4-amine (750 mg; 4.01 mmol) in DMF (15 mL) was purged with N₂. Copper(I) cyanide (1.08 g; 12.03 mmol) was added, the solution was purged again with N₂ and heated at 180° C. using one single mode microwave (Parr) with a power output ranging from 0 to 400W for 3 h [fixed old time]. The reaction mixture was poured onto an aqueous solution of K₂CO₃ 10% and EtOAc. The mixture was filtered through a pad of Celite® and the filtrate was extracted with EtOAc. The organic layer was decanted, washed with brine, dried over MgSO₄, filtered and the solvent was evaporated. The cake of Celite® was washed three times with DCM/MeOH (90:10), filtered and the solvent was evaporated to give 82 mg of crude material as a green solid. The crude material was combined with that from a parallel reaction for the purification. The residue was purified by chromatography over silica gel (SiOH, GraceResolv®, 4 g, solid deposit (Celite®); Mobile phase: Heptane/EtOAc 60:40). The pure fractions were collected and the solvent was evaporated to give 73 mg of intermediate 531 (10% yield) as an off-white solid.

Example A69 Preparation of Intermediate 533

At 0° C. and under N₂, lithium aluminum hydride 1M in THF (22.2 mL; 22.20 mmol) was added dropwise to a solution of ethyl 5-amino-6-methylnicotinate (1.00 g; 5.55 mmol) in Me-THF (5 mL). The reaction mixture was stirred at 0° C. for 30 min, then at rt for 3 h. The mixture was cooled to 0° C. and ice-water (590 μL) was added then a cooled solution of NaOH 3N (590 μL) and ice-water (1.77 mL) were successively added dropwise at 0° C. DCM was added, then MgSO₄ and the mixture was stirred at room temperature overnight. The mixture was filtered through a pad of Celite® and the filtrate was evaporated to give 579 mg of intermediate 533 (76% yield) as a white solid.

Example A70 Preparation of Intermediate 535

To a solution of 3-amino-2-methylpyridine-5-carboxylic acid (400 mg; 2.63 mmol) in DCM (22 mL) were added DIPEA (906 μL; 5.26 mmol), 1-methylpiperazine (0.448 ml; 3.94 mmol) and COMU® ((1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate) (2.82 g; 6.57 mmol). The reaction was stirred at rt for 2 h. The mixture was evaporated in vacuo. The residue was crystallized with DCM, filtered and dried to give 0.53 g of intermediate 535 (86% yield).

Example A71 Preparation of Intermediate 537

Sodium methoxide, 30 wt % solution in MeOH, (2.10 mL; 11.04 mmol) was added to a solution of 5-fluoro-2-methyl-4-nitropyridine-1-oxide (950 mg; 5.52 mmol) in Me-THF (13 mL). The reaction mixture was heated at reflux for 2 h. The reaction was cooled down to rt, water and DCM were added. The mixture was extracted five times with DCM. The organic layer was washed with water, dried over MgSO₄, filtered and the solvent was evaporated to give 328 mg of crude material as a red solid. The crude was purified by chromatography over silica gel (SiOH, GraceResolv®, 4 g, Mobile Phase: DCM/MeOH/NH₄OH Gradient from 100:0:0 to 99:1:0.1). The pure fractions were collected and the solvent was evaporated to give 98 mg of intermediate 537 (10% yield) as a yellow solid.

Preparation of Intermediate 538

A mixture of intermediate 537 (97 mg; 0.53 mmol) and Pd/C (10% wt., 24 mg; 0.23 mmol) in MeOH (12 mL) was hydrogenated at rt in a pressure vessel reactor (3 bar H₂) for 4 h. Hydrogenation of the reaction mixture was continued overnight. The catalyst was filtered through a pad of Celite®. The Celite® was washed with MeOH. Pd/C (10% wt., 24 mg; 0.23 mmol) was added to the filtered liquor and the reaction mixture was hydrogenated once more overnight plus 4 hours. Filtering, re-charging with fresh catalyst (Pd/C (10% wt., 24 mg; 0.23 mmol)) and hydrogenating overnight was repeated a further 2 times. The catalyst was filtered through a pad of Celite®. The Celite® was washed with DCM/MeOH and the filtrate was evaporated to give 62 mg of a mixture of intermediate 538 and 538′ (85% yield) as a pale yellow oil.

Example A72 Preparation of Intermediate 553

Thionyl chloride (9.46 mL, 130.288) was added dropwise to a solution of DL-Proline in EtOH (75 mL) cooled in an ice bath. The reaction mixture was allowed to reach rt and then heated to reflux for 16 h. The solvent was evaporated and the residue was diluted in EtOAc and washed with an aqueous solution of Na₂CO₃ and brine. The organic layer was separated, dried over MgSO₄ and removed under reduced pressure to yield intermediate 553.

Preparation of Intermediate 554

To a solution of intermediate 553 (1.00 g; 6.98 mmol) in THF:MeOH 9:1 (69.00 mL) with 3 A molecular sieves (1.00 g) was added (1-ethoxycyclopropoxy) trimethylsilane (4.21 mL; 20.95 mmol), AcOH (4.79 mL; 83.81 mmol) and sodium cyanoborohydride (1.32 g; 20.95 mmol) at room temperature. The reaction was heated to 65° C. for 16 h. The suspension was filtered and concentrated. Thre crude was diluted in saturated aqueous NaHCO₃ and extracted with EtOAc. The organic layer was dried over MgSO₄, filtered and removed under reduced pressure to give 1.07 g of intermediate 554 (84% yield, colorless oil).

Preparation of Intermediate 555

Lithium borohydride (630 mg, 28.923 mmol) was added to a solution of intermediate 554 (1.06, 5.785 mmol) in THF (30 mL) stirred at rt. The reaction mixture was stirred at 55° C. overnight. The reaction mixture was cooled, quenched with water. A solution of NaOH 10% was added and extracted with EtOAc. The organic layer was separated, dried over MgSO₄, filtered and removed under reduced pressure to yield intermediate 555 as a colorless oil. (678 mg, 83% yield).

Example A73 Preparation of Intermediate 569

To a solution of intermediate 522 (300 mg; 1.48 mmol) in DCM (5.00 mL) was added DMF (catalytic drop) at rt. To the solution was added oxalyl chloride (0.188 mL; 2.22 mmol) at 0° C. The solution was stirred at rt for 1 hour. The reaction was concentrated to give 327 mg of intermediate 569 (100% yield) as a yellow oil.

Preparation of Intermediate 570

To the solution of pyrrolidine and Et₃N (0.62 mL; 4.44 mmol) in DCM (5.00 mL) was added intermediate 569 (327 mg; 1.48 mmol) at 0° C. The reaction was stirred at room temperature for 16 hours. To the reaction was added water (100 mL). The mixture was extracted twice with EtOAc (100 mL). The organic layer was washed with brine (100 mL). Then the organic phase was dried over anhydrous Na₂SO₄. After filtering, the organic phase was concentrated. The crude product was purified by column chromatography over silica gel (Mobile phase: petroleum ether:EtOAc, 1:1). The pure fractions were collected and the solvent was evaporated under vacuum. The aqueous layer was concentrated to give 230 mg of intermediate 570 (61% yield) as a yellow solid.

The intermediates in the Table below were prepared by using an analogous method starting from the respective starting materials. The most relevant minor deviations to the referenced method are indicated as additional information in the column ‘Yield (%)’.

Intermediate Mass Yield number Structure (mg) (%) Intermediate 576

— — From intermediate 569 and intermediate 575

Preparation of Intermediate 571

Intermediate 570 (380 mg; 1.48 mmol) was suspened in MeOH (16.00 mL) and H₂O (4.00 mL). Iron (413 mg; 7.41 mmol) and NH₄Cl (792 mg; 14.81 mmol) were added. The mixture was refluxed for 2 hours. The mixture was cooled to rt and filtered. The filtrate was concentrated. The crude product was purified by column chromatography over silica gel (mobile phase petroleum ether:EtOAc, 1:1). The combined fractions containing pure product were concentrated to give 260 mg intermediate 571 (78% yield) as a yellow solid.

The intermediates in the Table below were prepared by using an analogous method starting from the respective starting materials. The most relevant minor deviations to the referenced method are indicated as additional information in the column ‘Yield (%)’.

Intermediate Mass Yield number Structure (mg) (%) Intermediate 577

— —

Example A74 Preparation of Intermediate 574

To the solution of (RS)—N—BOC-3-hydroxypyrrolidine (5.00 g, 26.704 mmol) and imidazole (4.55 g, 66.76 mmol) in DCM (50 mL) was added tert-butyldimethylchlorosilane (4.83 g, 32.045 mmol) at 0° C. The reaction was stirred at rt for 16 hours. The reaction was extracted three times with ethyl acetate (1000 mL). The combined organic layer was washed with brine (1000 mL). The organic phase was dried over anhydrous Na₂SO₄. The organic layer was concentrated. The crude product was purified by column chromatography over silica gel (EtOAc). The fractions containing pure product were combined and concentrated to give 7.0 g of intermediate 574 (87% yield) as a clear oil.

Preparation of Intermediate 575

To the solution of intermediate 574 in 40 mL of DCM was added 20 mL of TFA at 0° C. The solution was stirred at 0° C. for 2 hours. To the reaction was added NaHCO₃ aq. to basicify to pH=8. The reaction was concentrated to give a residue. The residue was washed with EtOAc. The organic layer was concentrated to give 4.00 g of intermediate 575 (Quant. Yield) as a yellow oil. The product was used in subsequent reactions without further purification.

Example A75 Preparation of Intermediate 579

Intermediate 578 was stirred in TBAF (1M) at rt. The reaction was concentrated to give 160 mg of intermediate 579 (92% yield).

Example A76 Preparation of Intermediate 580

DIPEA (2.50 mL; 14.50 mmol) was added to a solution of 3-amino-2-methoxypyridine (1.50 g; 12.08 mmol) and 2,4-dichloro-1,3,5-triazine (1.81 g; 12.08 mmol) in acetone at 0° C. The reaction mixture allowed to warm up to rt and stirred under nitrogen for 12 hours. The mixture was evaporated to give 3.00 g of crude material (yellow solid). This crude was combined with that from 2 parallel reactions for further purification by column chromatography (Mobile phase: Petroleum ether/ethyl acetate, Gradient from 100:0 to 20:80). The desired fractions were collected and the solvent was removed to give 780 mg intermediate 580 (27% yield) as a yellow solid.

Preparation of intermediate 581

To a mixture of intermediate 5R (988 mg; 1.87 mmol), intermediate 580 (400 mg; 1.68 mmol) and NaHCO₃ (3.74 mL; 7.48 mmol) in 1,4-dioxane (12.00 mL) was added Pd(dppf)Cl₂ (137 mg; 0.19 mmol) under N₂. The mixture was stirred at 80° C. for 12 h. The reaction was poured into water (30 ml) and extracted four times with EtOAc (40 mL). The organic layers were dried over Mg₂SO₄, filtered and concentrated to give 1.2 g of crude material. This crude was combined with that from 2 parallel reactions for further purification by column chromatography (Mobile phase: Petroleum ether/ethyl acetate Gradient from 100:0 to 0:100). The desired fractions were collected and the solvent was removed to give 330 mg intermediate 581 (24% yield) as a yellow solid.

Example A77 Preparation of Intermediate 582

To a solution of 2-amino-3-bromobenzonitrile (30.0 g) in THF (240 mL) was added sodium tert-butoxide (1.1 eq.) and the mixture was stirred at −5 to 5° C. for 1 hour. A solution of intermediate 3a in THF (85.0 g) was then added dropwise and the mixture was stirred for 2-4 hours monitoring the conversion by HPLC. Water (210 mL) was then added dropwise and the mixture was concentrated to remove most of THF.

Heptane (300 mL) was then added and the mixture was stirred for 30 min. After phase separation, the organic layer was washed with water (210 mL), concentrated to 2-3 volumes and filtered through a pad of silica gel (60 g), washing the pad with heptane (300 mL), affording 63.3 g of intermediate 582.

Preparation of Intermediate 583

To a solution of intermediate 582 (50.0 g) in dry THF (500 mL) was added dimethylaminopyridine (0.5 eq.) and the temperature was adjusted to 65-70° C. Di-tert-butyldicarbonate (2.2 eq.) was then added and the mixture was stirred for 2 hours monitoring the conversion by HPLC. Water (350 mL) was added and the mixture was concentrated to 350-400 mL. Heptane (500 mL) was added and the pH was adjusted by addition of 20% aqueous AcOH to 4-6. The layers were separated and water (350 mL) was added. After pH adjustment to 7-8 with aqueous 8% NaHCO₃, the layers were separated and the organic layer was washed with water (350 mL) and concentrated to afford 64 g (quantitative) of intermediate 583.

Example A78 Preparation of Intermediate 13i

In a sealed vessel, a mixture of intermediate 7R (214.00 mg, 0.52 mmol) in 1,4-dioxane (10 mL) was purged with N₂. Intermediate 12i (175.00 mg, 0.78 mmol) and Cs₂CO₃ (336.02 mg, 1.03 mmol) were successively added and the suspension was degassed after each addition. Then, Pd(OAc)₂ (11.58 mg, 0.052 mmol) and BINAP (32.11 mg, 0.052 mmol) were added. The reaction mixture was degassed with N₂ and stirred at 120° C. (pre-heated bath) for 3 h, cooled to rt, poured onto iced water and extracted with EtOAc. The organic layer was decanted, washed with brine, dried over MgSO₄, filtered over a pad of Celite® and evaporated to dryness. The residue was purified by column chromatography on silica gel (irregular SiOH, 25 g, mobile phase: DCM/MeOH, gradient from 95:5 to 90:10). The pure fractions were collected and evaporated to dryness to give 234 mg of intermediate 13i (75% yield, 89% purity based on LC/MS) used as it for the next step.

The intermediates in the Table below were prepared by using an analogous method starting from the respective starting materials. The most relevant minor deviations to the referenced method are indicated as additional information in the column ‘Yield (%)’.

Intermediate number Structure Mass (mg) Yield (%) Intermediate 17i

107 66 From intermediate 7R and intermediate 16i Intermediate 20i

668 (89% purity based on LC/MS) 95 Procedure with Me- THF as solvent and T = 85° C. From intermediate 7R and intermediate 19i Intermediate 23i

127 (79% purity based on LC/MS) off-white solid 67 Procedure with Me- THF as solvent and T = 85° C. From intermediate 7R and intermediate 22i Intermediate 36i

144 (84% purity based on LC/MS) 24 From intermediate 7R and 3-amino-2(1H)- pyridinone Intermediate 59i

245 brown oil 32 Procedure with T = 95° C. From intermediate 7 and 3-amino-5-chloro-1- methyl-2(1H)-pyridinone Intermediate 62i

215 66 From intermediate 7R and intermediate 61i Intermediate 65i

110 81 From intermediate 7R and intermediate 64i Intermediate 68i

500 73 From intermediate 7R and intermediate 67i Intermediate 71i

193 72 From intermediate 7R and intermediate 70i Intermediate 74i

203 85 From intermediate 7R and intermediate 73i Intermediate 78i

700 LC/MS purity 65% Combined with another crude — From intermediate 7R and intermediate 77i Intermediate 87i

211 73 Procedure at 120° C. for 18 h From intermediate 7R and intermediate 86i Intermediate 100i

415 57 From intermediate 7R and intermediate 99i

Example A79 Preparation of Intermediate 26i

A suspension of intermediate 6R (0.45 g, 0.87 mmol), intermediate 25 (251.90 mg, 1.31 mmol), Pd(OAc)₂ (19.61 mg, 0.087 mmol), BINAP (54.40 mg, 0.087 mmol) and Cs₂CO₃ (853.88 mg, 2.62 mmol) in Me-THF (9 mL) was purged with N₂ and stirred at 85° C. for 2 h. The mixture was cooled down to rt, combined with another batch (from 50 mg of intermediate 6R) and filtered on a pad of Celite®. The cake was washed with EtOAc and the filtrate was evaporated in vacuo to give a brown foam. The residue (849 mg) was purified by column chromatography on silica gel (irregaular SiOH, 15-40 μm, 40 g, dry loading on Celite®, mobile phase: heptane/EtOAc, gradent from 85:15 to 50:50). The fractions containing the product were combined and evaporated to dryness to give 629 mg of intermediate 26i (93% yield, 94% purity based on LC/MS, off-white foam).

The intermediates in the Table below were prepared by using an analogous method starting from the respective starting materials. The most relevant minor deviations to the referenced method are indicated as additional information in the column ‘Yield (%)’.

Intermediate number Structure Mass (mg) Yield (%) Intermediate 30i

683 (98% purity based on NMR) yellow solid 95 From intermediate 6R and intermediate 29i Intermediate 34i

476 off-white foam 76 From intermediate 6R and intermediate 33i Intermediate 37i

876 clear brown foam Quant. Procedure with 1,4- dioxane as solvent and T = 100° C. From intermediate 6R and 3-amino-1,5- dimethyl-2(1H)-pyridinone (intermediate 102i) Intermediate 41i

270 greenish film 44 Procedure with 1,4- dioxane as solvent and T = 100° C. From intermediate 6R and intermediate 40i Intermediate 47i

186 (56% purity based on LC/MS) green oil — Procedure with 1,4- dioxane as solvent and T = 90° C. From intermediate 6R and intermediate 46i Intermediate 51i

490 (88% purity based on LC/MS) brown oil 97 Procedure with 1,4- dioxane as solvent and T = 90° C. From intermediate 6R and intermediate 50i Intermediate 53i

542 (83% purity based on LC/MS) 90 Procedure with 1,4- dioxane as solvent and T = 95° C. From intermediate 6R and 3-amino-5-chloro-1- methyl-2(1H)-pyridinone Intermediate 57i

734 (86% purity based on LC/MS) brown oil — Procedure with 1,4- dioxane as solvent and T = 95° C. From intermediate 6R and intermediate 56i Intermediate 82i

240 44% Procedure with 1,4- dioxane as solvent and T = 80° C. From intermediate 6R and intermediate 81i

Example A80 Preparation of Intermediate 27i

To a solution of intermediate 26i (609.00 mg, 0.89 mmol) in DCM (20 mL), TFA (2.00 mL, 26.1 mmol) was added and the mixture was stirred at rt for 20 min. The mixture was combined with another batch (from 616 mg of intermediate 26i). The mixture was poured into a saturated solution of NaHCO₃. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were dried over MgSO₄, filtered off and evaporated in vacuo. The residue (550 mg, orange foam) was purified by column chromatography on silica gel (irregular SiOH, 15-40 μm, 40 g, dry loading on Celite®, mobile phase gradient: from heptane 95%, EtOAc/MeOH (9:1) 5% to heptane 60%, EtOAc/MeOH (9:1) 40%). The fractions containing the product were combined and concentrated under vacuum to give 429 mg of intermediate 27i (81% yield, off-white foam.

The intermediates in the Table below were prepared by using an analogous method starting from the respective starting materials. The most relevant minor deviations to the referenced method are indicated as additional information in the column ‘Yield (%)’.

Intermediate number Structure Mass (mg) Yield (%) Intermediate 31i

456 off-white solid 79 From intermediate 30i Intermediate 35i

460 off-white solid 84 From intermediate 34i Intermediate 42i

220 orange oil 96 Procedure with DCM/TFA (6:1, v/v) From intermediate 41i Intermediate 48i

70 (72% purity based on LC/MS) 43 Procedure with DCM/TFA (5:2, v/v) From intermediate 47i Intermediate 52i

310 (94% purity based on LC/MS) 74 Procedure with DCM/TFA (5:2, v/v) From intermediate 51i Intermediate 54i

390 (66% purity based on LC/MS) 85 Procedure with DCM/TFA (5:2, v/v) From intermediate 53i Intermediate 58i

308 green oil 73 Procedure with DCM/TFA (9:1, v/v) From intermediate 57i Intermediate 83i

250 97 Procedure with DCM/TFA (5:1, v/v) From intermediate 82i Intermediate 105i

260 LCMS 65% quantitative From intermediate 104i

Example A81 Preparation of Intermediate 38i

A mixture of intermediate 37i (876.00 mg, 1.35 mmol) in Me-THF (6 mL) was treated with TBAF (1M in THF) (2.10 mL, 2.10 mmol) and stirred at rt for 18 h, leading to precipitation. The precipitate was filtered off, washed with MeTHF and dried to afford 150 mg of intermediate 38i (22%). The filtrate was extended with DCM and concentrated to afford a red solution. It was purified by column chromatography on silica gel (iregular SiOH 30 μm, 80 g, liquid injection with a mixture of Me-THF/DCM, mobile phase EtOAc/MeOH, gradient from 100:0 to 95:5 in 20 CV). The fractions containing the product were combined and evaporated to dryness to give additional 439 mg of intermediate 38i (65% yield, pale yellow solid).

Example A82 Preparation of Intermediate 8i

In a sealed tube, a mixture of 2-hydroxy-5-methyl-3-nitropyridine (1.00 g, 6.49 mmol), (2-bromoethoxy)-tert-butyldimethylsilane (2.80 mL, 12.98 mmol) and K₂CO₃ (2.70 g, 19.46 mmol) in DMF (13 mL) was stirred at 60° C. for 2 h. The reaction mixture was cooled down to rt, poured onto a mixture of water and brine, then extracted with Et₂O. The organic layer was decanted, washed with brine, dried over MgSO₄, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel (irregular SiOH, 80 g, mobile phase: heptane/EtOAc, gradient from 80:20 to 60:40). The pure fractions were collected and evaporated to dryness to give 1.68 g of intermediate 8i (83% yield, 94% purity based on LC/MS).

Preparation of Intermediate 9i

TBAF (1 M in THF) (8.64 mL, 8.64 mmol) was added to a solution of intermediate 8i (1.35 g, 4.32 mmol) in Me-THF (40 mL). The reaction mixture was stirred for 1 h and evaporated to dryness. The residue was purified by column chromatography on silica gel (irregular SiOH, 40 g, mobile phase: 5% MeOH, 95% DCM). The pure fractions were collected and evaporated to dryness. The residue was taken up with a mixture of CH₃CN/Et₂O and the precipitate was filtered and dried to give 535 mg of intermediate 9i (62% yield).

The intermediate in the Table below was prepared by using an analogous method starting from the respective starting material.

Intermediate Mass Yield number Structure (mg) (%) Intermediate 94i

250 69 From intermediate 93i

Preparation of Intermediate 10i

A mixture of intermediate 9i (300.00 mg, 1.51 mmol) and SOCl₂ (0.22 mL, 3.03 mmol) in DCM (5 mL) was stirred at rt for 3 h and the reaction mixture was evaporated to dryness to give 300 mg of intermediate 10i (91% yield).

The intermediate in the Table below was prepared by using an analogous method starting from the respective starting material.

Intermediate Mass Yield number Structure (mg) (%) Intermediate 95i

256 98 From intermediate 94i

Preparation of Intermediate 11i

A mixture of intermediate 10i (300.00 mg, 1.38 mmol), 3-fluoroazetidine HCl salt (185.38 mg, 1.66 mmol) and DIEA (716.00 μL, 4.15 mmol) in CH₃CN (8 mL) was refluxed for 1 h in a sealed tube. The reaction mixture was evaporated to dryness and the residue was purified by column chromatography on silica gel (irregular SiOH, 12 g, mobile phase: DCM/MeOH, gradient from 100:0 to 90:10). The pure fractions were collected and evaporated to dryness to give 200 mg of intermediate 11i (57% yield).

The intermediates in the Table below were prepared by using an analogous method starting from the respective starting materials.

Inter- mediate Mass Yield number Structure (mg) (%) Inter- mediate 15i

177 (87% purity based on LC/MS) 53 From intermediate 10i and cis-2,6- dimethylmorpholine Inter- mediate 60i

369 78 From intermediate 10i and cis-2,6- dimethylpiperazine Inter- mediate 63i

177 40 From intermediate 10i and 3,3-difluoroazetidine hydrochloride Inter- mediate 69i

227 Brown oil 53 From intermediate 10i and 1-methylpiperazine Inter- mediate 72i

257 59 From intermediate 10i and homomorpholine hydrochloride Inter- mediate 96i

195 65 From intermediate 95i and 3-fluoroazetidine hydrochloride

Preparation of Intermediate 12i

A mixture of intermediate 11i (264.00 mg, 1.03 mmol), iron powder (288.81 mg, 5.17 mmol) and NH₄Cl (221.30 mg, 4.14 mmol) in a mixture of EtOH (9 mL) and distilled water (4.5 mL) was heated at 80° C. for 2 h. Then, the mixture was cooled down to rt, diluted with DCM and filtered through a pad of Celite®. The organic layer was basified with a 10% aqueous solution of K₂CO₃, decanted, dried over MgSO₄, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel (irregular SiOH, 25 g, mobile phase: 5% MeOH, 95% DCM). The pure fractions were collected and evaporated to dryness to give 175 mg of intermediate 12i (75% yield, 96% purity based on LC/MS).

The intermediates in the Table below were prepared by using an analogous method starting from the respective starting materials. The most relevant minor deviations to the referenced method are indicated as additional information in the column ‘Yield (%)’.

Intermediate number Structure Mass (mg) Yield (%) Intermediate 16i

100 63 with EtOH/ water (5:3, v/v) From intermediate 15i Intermediate 19i

485 65 with EtOH/ water (1:1, v/v) From intermediate 18i Intermediate 22i

69 beige solid 51 with EtOH/ water (1:1, v/v) From intermediate 21i Intermediate 25i

603 black oil 90 with EtOH/ water (1:1, v/v) From intermediate 24i Intermediate 29i

504 (70% purity based on LC/MS) black solid 68 with EtOH/ water (1:1, v/v) From intermediate 28i Intermediate 33i

828 brown oil 66 with EtOH/ water (1:1, v/v) From intermediate 32i Intermediate 40i

255 dark green oil 96 with EtOH/ water (1:1, v/v) From intermediate 39i Intermediate 46i

85 green residue 54 with EtOH/ water (1:1, v/v) From intermediate 45i Intermediate 50i

235 brown oil 54 with EtOH/ water (1:1, v/v) From intermediate 49i Intermediate 56i

174 (88% purity based on LC/MS) brown oil 73 with EtOH/ water (1:1, v/v) From intermediate 55i Intermediate 61i

200 dark brown 62 From intermediate 60i Intermediate 64i

177 brown 40 From intermediate 63i Intermediate 70i

160 80 From intermediate 69i Intermediate 73i

143 63 From intermediate 72i Intermediate 86i

175 86 Procedure with EtOH/ water (7:4, v/v) From intermediate 85i Intermediate 97i

60 36 From intermediate 96i Intermediate 99i

307 80 From intermediate 98i

Example A83 Preparation of Intermediate 14i

MsCl (249.24 μL, 3.21 mmol) was added at 5° C. to a suspension of intermediate 9 (530.00 mg, 2.67 mmol) and TEA (743.47 μL, 5.34 mmol) in DCM (13 mL), and the reaction mixture was stirred at 5° C. for 30 min. Then, a 10% aqueous solution of NH₄Cl (2 mL) and DCM were added. The organic layer was filtered over Chromabond® and evaporated to dryness to give 631 mg of intermediate 14i (85% yield, 82% purity based on LC/MS) used as it for the next step.

Example A84 Preparation of intermediate 18i

To a suspension of 5-fluoro-2-hydroxy-3-nitropyridine (1.03 g, 6.49 mmol) in DMF (13 mL) at rt, K₂CO₃ (3.59 g, 25.95 mmol) then N-(2-chloroethyl)morpholine hydrochloride (2.42 g, 12.98 mmol) were added, and the reaction mixture was stirred at 60° C. for 2 h. The mixture was cooled down to rt and filtered off. The filtrate was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO₄, filtered and evaporated in vacuo. The residue was purified by column chromatography on silica gel (irregular SiOH, 15-40 μm, 120 g, mobile phase gradient: from heptane/EtOAc/MeOH: 100/0/0 to 0/80/20). The pure fractions were mixed and the solvent was evaporated to give and 0.846 g of intermediate 18i (48% yield).

The intermediates in the Table below were prepared by using an analogous method starting from the respective starting materials. The most relevant minor deviations to the referenced method are indicated as additional information in the column ‘Yield (%)’.

Intermediate number Structure Mass (mg) Yield (%) Intermediate 21i

155 yellow solid 17 with T = rt From 2-hydroxy-5-methyl-3- nitropyridine and 2-chloromethyl-1- methyl-1H-imidazole, HCl salt Intermediate 28i

829 (intermediate 28) yellow solid 47 with T = rt From 2-hydroxy-5-methyl-3- nitropyridine and 2-(chloromethyl)-1- cyclopropyl-1H-imidazole, HCl salt Intermediate 32i

1500 86 From 2-hydroxy-5-methyl-3-nitropyridine and N-(2-chloroethyl)morpholine, HCl salt Intermediate 39i

310 yellow oil 51 with T = rt From 3-nitro-2(3H)-pyridinone and 1- Bromo-3-methoxypropane Intermediate 49i

510 yellow solid 32 From 5-chloro-2-hydroxy- 3-nitropyridine and 2- Bromo-N,N- dimethylethylamine hydrobromide salt Intermediate 55i

293 brown solid 44 with Na₂CO₃ as a base From 5-chloro-2-hydroxy- 3-nitropyridine and 2- bromoethyl methyl ether Intermediate 66i

483 80% purity based on ¹H nmr 56 From 5-methyl-2-hydroxy-3-nitropyridine and 4-(2-chloro-1-methylethyl)morpholine Intermediate 85i

229 64 Procedure at 60° C. for 5 h From 5-methyl-2-hydroxy-3- nitropyridine and intermediate 84i Intermediate 93i

568 28 From 5-fluoro-2-hydroxy-3-nitropyridine and (2-bromoethoxy)-tert-butyldimethylsilane Intermediate 98i

365 51 From 5-methyl-2-hydroxy-3- nitropyridine and 3-bromomethyl- 3-methyloxetane Intermediate 101i

500 91 Procedure with T = rt From 5-methyl-2- hydroxy-3-nitropyridine and iodo-methane

Example A85 Preparation of intermediate 24i

To a suspension of 2-hydroxy-5-methyl-3-nitropyridine (0.60 g, 3.89 mmol) in DMF (8 mL) at rt, K₂CO₃ (1.61 g, 11.7 mmol), NaI (58.40 mg, 0.39 mmol) were added then (2-bromoethyl)cyclopropane (0.87 g, 5.84 mmol) and the reaction mixture was stirred at 60° C. for 3 h. The mixture was combined with two other batches (from each 50 mg of 2-hydroxy-5-methyl-3-nitropyridine) and filtered on a pad of Celite®. The cake was washed with EtOAc and the filtrate was evaporated in vacuo to give a brown oil. The residue was purified by column chromatography on silica gel (irregular SiOH, 15-40 μm, 50 g, dry loading on Celite®, mobile phase gradient: from heptane 90%, EtOAc/MeOH (9:1) 10% to heptane 50%, EtOAc/MeOH (9:1) 50%). The fractions containing the product were combined and evaporated to dryness to give 775 mg of intermediate 24i (77% yield, orange gum).

Example A86 Preparation of Intermediate 43i

In sealed glassware, 5-chloro-2-hydroxy-3-nitropyridine (2.00 g, 11.50 mmol) and ethyl bromoacetate (1.53 mL, 13.80 mmol) were diluted in acetone (40 mL). K₂CO₃ (1.90 g, 13.80 mmol) was added to the solution and the mixture was refluxed for 17 h with stirring. The reaction mixture was diluted with water and extracted twice with EtOAc. The organic layers were combined and washed with brine, dried over MgSO₄ and filtered. The solvent was removed under reduced pressure. The residue (2.62 g, brown residue) was purified by column chromatography on silica gel (irregular SiOH 15-40 μm, 120 g, dry load on Celite®, mobile phase gradient: from DCM 100% to DCM 90%, MeOH (+aq. NH₃ 5%) 10%). The fractions containing the products were combined and evaporated to dryness to give 1.65 g of intermediate 43i (55% yield, yellow solid).

Preparation of Intermediate 44i

A mixture of intermediate 43i (700.00 mg, 2.69 mmol) and LiOH monohydrate (169.10 mg, 4.03 mmol) in a mixture of Me-THF (19 mL) and distilled water (7.7 mL) was stirred at rt for 16 h. HCl (3M in cyclopentyl methyl ether) (0.67 mL, 1.79 mmol) was added and the mixture was evaporated to dryness. The residue (brown oil) was purified by column chromatography on silica gel (irregular SiOH, 15-40 μm, 24 g, dry loading on Celite®, mobile phase gradient: from DCM 100% to DCM 80%, MeOH/AcOH (90:10) 20%). The fractions containing the product were combined and evaporated to dryness to give 380 mg of intermediate 44i (61% yield, brown solid).

Preparation of Intermediate 45i

In a sealed tube, intermediate 44i (380.00 mg, 1.63 mmol) and dimethylamine (0.98 mL, 1.96 mmol) were diluted in DMF (19 mL). Then, HATU (1.37 g, 3.59 mmol) and DIEA (713.40 μL, 4.09 mmol) were added and the mixture was stirred at 70° C. for 16 h. The mixture was concentrated to dryness, diluted with DCM and basified with an aqueous saturated solution of NaHCO₃. The layers were separated and the organic layer was dried over MgSO₄, filtered and the solvent was removed under reduced pressure to give. The residue was purified by column chromatography on silica gel (irregular SiOH 15-40 μm, 24 g, dry load on Celite®, mobile phase DCM/MeOH, gradient from 100:0 to 85:15). The fractions containing the product were combined and evaporated to dryness. The residue (brown oil) was purified again by column chromatography on silica gel (irregular SiOH 15-40 μm, 24 g, dry load on Celite®, mobile phase heptane/EtOAc, gradient from 20:80 to 0:100) to give 80 mg of intermediate 45i as a pale yellow solid (19%).

Example A87 Preparation Intermediate 67i

Intermediate 66i (460 mg, 1.64 mmol) with Raney Nickel (67 mg) as a catalyst in MeOH (51 mL) was hydrogenated at rt overnight under 1.5 bar of H₂. The catalyst was filtered off and the filtrate was evaporated, yielding: 0.411 g of intermediate 67i.

Example A88 Preparation Intermediate 75i

To a solution of 5-bromo-2-hydroxy-3-nitropyridine (14 g, 63.9 mmol) in THF (200 mL) at room temperature was added tBuOK (7.5 g, 67.1 mmol), and stirred for 0.5 hour. (Bromomethyl)cyclopropane (8.7 mL, 92 mmol) and DMF (200 mL) were added to the suspension and the resulting mixture was warmed to 85° C. The mixture was stirred overnight at 85° C. Water (600 mL) was added, and extracted with ethyl acetate (500 mL*3). The organic phase was washed with water, brine, dried over Na₂SO₄, filtered, and evaporated in vacuum to give the crude compound. The crude (18 g) intermediate was purified by column chromatography over silica gel (eluent: Petrol ether/Ethyl acetate=2/3). The desired fractions were evaporated in vacuum to give the product as a brown solid: 13.0 g of intermediate 75i, yield 74.5%.

Preparation Intermediate 76i

To a solution of 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (1.15 g, 5.1 mmol) in water (2 mL) and 1,4-dioxane (10 mL) was added K₃PO₄ (3.3 g, 15.4 mmol), intermediate 75 (1.4 g, 5.1 mmol) and Pd-118 (334 mg, 0.51 mmol) under N₂. The mixture was stirred at 60° C. overnight under N₂. The mixture was poured into water (30 mL) and extracted with ethyl acetate (50 mL*3). The organic layer was washed with water (25 mL) and then brine (25 mL), dried over MgSO₄, and evaporated under vacuum. The residue was purified by flash column chromatography over silica gel (eluent: petroleum ether/ethyl acetate from 100/0 to 0/100; ethyl acetate/MeOH (0.1% NH₄OH) from 100/0 to 70/30). The desired fractions were collected and the solvent was concentrated to dryness under vacuum to give product as yellow solid. Yield: 900 mg (51% yield) of intermediate 76i.

Preparation Intermediate 77i

A mixture of intermediate 76i (800 mg, 2.3 mmol) in MeOH (50 mL) was hydrogenated at rt (20 Psi) with Pd(OH)₂/C (160 mg) as a catalyst. After uptake of H₂ (4 equiv), the mixture was stirred overnight at 30° C. The catalyst was filtered off through celite and the filtrate was evaporated to give the product as a black oil. The crude product was combined with a another batch from 100 mg of intermediate 76i.

The residue was purified by preparative high-performance liquid chromatography over column: DuraShell 150*25 mm*5 um. Conditions: eluent A: water (+0.05% ammonia hydroxide v/v); eluent B: MeCN—starting from: A (88%) and B (12%) up to: A: (58%) and B (42%). Gradient Time (min) 10; 100% B Hold Time (min) 2.5; Flow Rate (ml/min) 25.

The pure fractions were collected and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to dryness to give the product as a yellow oil. Yield: 400 mg (56.8% yield) of intermediate 77i

Example A89 Preparation Intermediate 79i

A mixture of intermediate 75i (5 g, 18.3 mmol), TEA (5.6 g, 54.9 mmol) and PdCl₂(dppf).DCM (1.5 g, 1.8 mmol) in MeOH (120 mL) was stirred at 80° C. under an atmosphere of CO (0.5 MPa) overnight. The mixture was filtered through Celite®, and evaporated in vacuum to give the crude compound. The crude compound was purified by column chromatography over silica gel (eluent: Petroleum ether/ethyl acetate=1/2). The desired fractions were evaporated in vacuum to give the compound as a brown solid. Intermediate 79i, 1.74 g, yield 39.6%.

Preparation Intermediate 80i

A solution of intermediate 79i (0.8 g, 3.6 mmol) and NaOH (158 mg, 3.96 mmol) in THF (50 mL) and water (5 mL) was stirred at room temperature overnight. The mixture was evaporated in vacuum to give the desired compound as a white solid. Intermediate 80i, 800.0 mg, yield 90.5%.

Preparation Intermediate 81i

To a solution of intermediate 80i (0.8 g, 3.5 mmol), MeNH₂ in THF (5.2 mL, 10.4 mmol) and Pybrop (4.9 g, 10.5 mmol) in DMF (30 mL) was added DIPEA (1.35 g, 10.4 mmol). The reaction mixture was stirred at room temperature overnight. Water (60 mL) was added to the reaction mixture, and extracted with ethyl acetate (50 mL*3). The organic phase was washed with brine, dried over Na₂SO₄, filtered, and evaporated in vacuum to give the 0.9 g of crude compound. The residue was purified by high performance liquid chromatography (Column: Boston Green ODS 150*30 5 u Conditions: eluent A: water (0.05% HCl)-ACN; eluent B: MeCN—starting from: A (100%) and B (0%) up to: A: 70% and B (30%). Gradient Time (min) 12. 100% B; Hold Time (min) 2.2; Flow Rate (ml/min) 25).

The desired fraction was collected, evaporated in vacuum to give the desired compound as a white solid. Intermediate 81i, 0.59 g, yield 76.7%.

Example A90 Preparation of Intermediate 84i

A mixture of 4-methyl-3-(hydroxymethyl)morpholine hydrochloride (500 mg; 3 mmol) and thionyl chloride (1 mL; 13.8 mmol) in DCM (10 mL) was stirred at room temperature for 3 hours. Thionyl chloride (1 mL; 13.8 mmol) was added again and the reaction mixture was stirred for 18 hours more. The reaction mixture was evaporated to dryness yielding 500 mg (99%) intermediate 84i. Used as such in the next step without further purification.

Example A91 Preparation of Intermediate 92i

TFA (6 mL) was added dropwise at 5° C. to a solution of intermediate 334 (3.00 g, 7.79 mmol) in DCM (60 mL) and the reaction mixture was stirred at 5° C. for 1 h. The reaction mixture was diluted with DCM and poured onto a mixture of ice and 10% aqueous K₂CO₃. The insoluble material was filtered, washed with water then Et₂O and dried to give 1.93 g of intermediate 92i (87% yield).

Example A92 Preparation of Intermediate 103i

To a solution of intermediate 102i (370 mg, 2.68 mmol) in acetone (10 mL) was added 2,4-dichloro-1,3,5-triazine (402 mg, 2.68 mmol) and DIPEA (1 g, 8 mmol). The mixture was stirred at room temperature for 1.5 hours. The mixture was evaporated to give 1.37 g (crude product) of intermediate 103i.

Example A93

Preparation of Intermediate 102i

A mixture of intermediate 101i (500 mg, 2.97 mmol) in MeOH (10 mL) was hydrogenated at room temperature (15 psi) with Pd/C (50 mg) as a catalyst. After uptake of H₂ (1 eq, 18 hours), the catalyst was filtered off and the filtrate was evaporated to give 420 mg of a black oil (Quantitative yield).

Example A94 Preparation of Intermediate 108i

A suspension of intermediate 6R (0.4 g, 0.78 mmol), 2-(oxetan-3-yloxy)pyridin-3-amine (181 mg, 1.09 mmol), Pd(OAc)₂ (8.7 mg, 0.039 mmol), BINAP (24.2 mg, 0.039 mmol) and Cs₂CO₃ (759 mg, 2.33 mmol) in 1,4-dioxane (8.9 mL) in a sealed tube was purged with N₂ and stirred at 120° C. for 30 minutes using one single mode microwave (Biotage Initiator EXP 60) with a power output ranging from 0 to 400 W [fixed hold time]. The reaction mixture was cooled down to room temperature and partitionned between water and EtOAc. The organic layer was separated, dried over MgSO₄ and concentrated. The residue was purified by silica gel chromatography (irregular SiO₂, 40 g, gradient from heptane/EtOAc 90/10 to 0/100). The fractions containing the product were mixed and the solvent was concentrated, affording 0.538 g of intermediate 108i (83% yield, LCMS 97%).

Preparation of Intermediate 109i

TFA (0.958 mL; 12.5 mmol) was added at 5° C. to a solution of intermediate 108i (538 mg; 0.834 mmol) in DCM (8.6 mL). The reaction mixture was stirred at 5° C. for 1 hour. The mixture was diluted with DCM (50 mL) and poured onto a 10% aqueous solution of K₂CO₃. More DCM/MeOH was added (80/20; 200 mL) The organic layer was decanted, washed with a 10% aqueous solution of K₂CO₃, dried over MgSO₄, filtered and evaporated to dryness to give 0.454 g of intermediate 109i (100% yield).

B. Preparation of the Final Compounds Example B1 Preparation of Compound 1

To a solution of intermediate 8 (235.00 mg, 0.29 mmol) in DCM (3 mL), TFA (3 mL) was added and the reaction mixture was stirred at rt for 2 h. Then, the solution was concentrated in vacuo and neat TFA (3 mL) was added. The reaction mixture was stirred for a further 4 h. The reaction mixture was stirred for a further 1 h and the solution was concentrated in vacuo. The residue was treated with K₂CO₃ (242.00 mg, 1.75 mmol) in DMF (2 mL) for 1 h at 50° C. After further 30 min stirring at 50° C. the reaction mixture was partitioned between EtOAc and water and the organic layer was dried with Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography on silica gel (SiO₂, 10 g, mobile phase: cyclohexane/EtOAc, gradient from 100:0 to 0:100). The relevant fractions were joined and concentrated in vacuo.

This residue was submitted to mass directed auto purification system to give 43 mg of compound 1 (37% yield).

Example B2 Preparation of Compound 2

TFA (0.53 mL, 6.89 mmol) was added at 5° C. to a solution of intermediate 13 (274.00 mg, 0.46 mmol) in DCM (5 mL). The reaction mixture was stirred at 5° C. for 1 h, diluted with DCM (50 mL) and poured onto a 10% aqueous solution of K₂CO₃. More DCM/MeOH was added (80:20; 200 mL). The organic layer was decanted, washed with a 10% aqueous solution of K₂CO₃, dried over MgSO₄, filtered and evaporated to dryness. The residue (200 mg) was purified by column chromatography on silica gel (irregular SiOH, 25 g+5 g solid deposit; mobile phase: NH₄OH/MeOH/DCM, gradient from 0.2% NH₄OH, 2% MeOH, 98% DCM to 1% NH₄OH, 10% MeOH, 90% DCM). The pure fractions were collected and evaporated to dryness. The residue (170 mg) was purified again by column chromatography on silica gel (irregular SiOH, 25 g+5 g solid deposit; mobile phase: NH₄OH/MeOH/DCM, gradient from 0.4% NH₄OH, 4% MeOH, 96% DCM to 1.5% NH₄OH, 15% MeOH, 85% DCM). The pure fractions were collected and evaporated to dryness. The residue was taken up with CH₃CN and the precipitate was filtered and dried to give 101 mg of compound 2 (44% yield). M.P.=230° C. (K).

Alternatively, this compound could be obtained by the use of a mixture of TFA/DCM (1:1, v/v).

Preparation of Compound 3

A solution of intermediate 16 (355.00 mg, 0.68 mmol) in a mixture of DCM (5 mL) and TFA (2 mL) was stirred at rt for 2 h. The reaction mixture was quenched with a saturated solution of NaHCO₃ and poured in a mixture DCM/MeOH (95:5). The organic layer was separated, washed with a saturated solution of NaHCO₃, dried over MgSO₄ and evaporated in vacuo to give a black oil. The residue was purified by column chromatography on silica gel (irregular SiOH 15-40 μm, 120 g, mobile phase: DCM/(MeOH (5% aq NH₃)), gradient from 98:2 to 95:5). The fractions containing the product were combined and evaporated to dryness to give 60 mg of a beige solid. This solid was recrystallized from EtOH. After filtration on a glass frit, the solid was washed with Et₂O and dried in vacuo to give 49 mg of compound 3 (17% yield over 3 steps, off-white solid).

Preparation of Compound 4

A mixture of intermediate 19 (294.00 mg, 0.58 mmol) in a mixture of TFA (2 mL) and DCM (5 mL) was stirred at rt for 1 h. The mixture was basified with saturated aq. NaHCO₃. An extraction was performed with DCM. The organic layer was washed with brine, dried over MgSO₄, evaporated and purified by column chromatography on silica gel (irregular SiOH 15-40 μm, 80 g, liquid injection in DCM, mobile phase: DCM/(MeOH (10% aq NH₃)), gradient from 100:0 to 94:6 in 15 CV). The fractions containing the product were combined and evaporated to dryness to give 45 mg of compound 4 (19% yield over 3 steps, light yellow solid). M.P.=277° C. (DSC).

Preparation of Compound 10

TFA (0.56 mL) was added at 5° C. to a solution of intermediate 29 (290.00 mg, 0.49 mmol) in DCM (5 mL). The reaction mixture was stirred at 5° C. for 1 h, diluted with DCM (50 mL) and poured onto a 10% aqueous solution of K₂CO₃. More DCM/MeOH was added (80:20, 200 mL). The organic layer was decanted, washed with a 10% aqueous solution of K₂CO₃, dried over MgSO₄, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel (irregular SiOH, 40 g+5 g solid deposit, mobile phase: heptane/EtOAc/MeOH/DCM, gradient from 60% heptane, 1.5% MeOH, 38.5% EtOAc to 0% heptane, 3.5% MeOH, 96.5% EtOAc then 0% NH₄OH, 0% MeOH, 100% DCM to 1% NH₄OH, 10% MeOH, 90% DCM). The pure fractions were collected and evaporated to dryness to give 43 mg of compound 10 (18% yield). M.P.=231° C. (K).

Preparation of Compound 50

TFA (3.92 mL) was added dropwise to a solution of intermediate 164 (622.00 mg, 1.25 mmol) in DCM stabilized with amylene (21 mL) at 5° C. and the reaction mixture was stirred for 1 h at this temperature. The reaction mixture was quenched with a 10% aqueous solution of K₂CO₃ and extracted with DCM. The organic layer was decanted, filtered through Chromabond® and evaporated to dryness. The residue was purified by column chromatography on silica gel (irregular SiOH, 24 g, mobile phase: NH₄OH/MeOH/DCM gradient from 0.5% NH₄OH, 5% MeOH, 95% DCM to 1% NH₄OH, 10% MeOH, 90% DCM). The pure fractions were collected and evaporated to dryness. The residue was crystallized from CH₃CN/Et₂O and the precipitate was filtered and dried to give 213 mg of compound 50 (43% yield). M.P.=242 (DSC).

Preparation of Compound 59

TFA (1.5 mL) was added dropwise to a solution of intermediate 196 (260.00 mg, 0.52 mmol) in DCM (10 mL) at 5° C. and the reaction mixture was stirred for 1 h at this temperature. The reaction mixture was quenched with a 10% aqueous solution of K₂CO₃ and extracted with DCM. The insoluble material was filtered. The organic layer was decanted, dried over MgSO₄, filtered and evaporated to dryness. The residue was gathered with the insoluble material. The mixture was suspended in EtOH and sonicated for 15 min. The precipitate was filtered and dried to give 138 mg of compound 59 (66% yield). M.P.=234° C. (K).

Preparation of Compound 65

TFA (1.5 mL) was added dropwise to a solution of intermediate 221 (300.00 mg, 0.52 mmol) in DCM (10 mL) at 5° C. and the reaction mixture was stirred for 1 h at this temperature. The reaction mixture was quenched with a 10% aqueous solution of K₂CO₃ and extracted with DCM. The organic layer was decanted, dried over MgSO₄, filtered and evaporated to dryness. The residue was crystallized from CH₃CN and the precipitate was filtered and dried. The residue (178 mg) was purified by column chromatography on silica gel (irregular SiOH, 24 g, mobile phase: DCM/MeOH, gradient from 100:0 to 90:10). The pure fractions were collected and evaporated to dryness. The residue was crystallized from CH₃CN and the precipitate was filtered and dried. The residue (136 mg) was further purified by column chromatography on silica gel (irregular SiOH, 24 g, mobile phase: 0.5% NH₄OH, 10% MeOH, 50% EtOAc, 40% heptane). The pure fractions were collected and evaporated to dryness. The second filtrate was purified by column chromatography on silica gel (irregular SiOH, 24 g, mobile phase: 0.5% NH₄OH, 10% MeOH, 50% EtOAc, 40% heptane). The pure fractions were collected and evaporated to dryness. The residues were mixed and taken up with Et₂O. The precipitate was filtered and dried to give 155 mg of compound 65 (64% yield). M.P.=158° C. (K).

Preparation of Compound 140

A mixture of intermediate 430 (418.00 mg, 0.63 mmol) in a mixture of TFA (0.80 mL) and DCM (6 mL) was stirred at rt for 30 min. The mixture was basified with a saturated aqueous solution of NaHCO₃. An extraction was performed with DCM. The organic layer was washed with brine, dried over MgSO₄, evaporated and purified by column chromatography on silica gel (irregular SiOH 15-40 μm, 80 g, liquid injection with DCM, mobile phase: DCM/(MeOH (10% aq. NH₃)), gradient from 100:0 to 90:10 in 10 CV). The fractions containing the product were combined and concentrated under vaccum to give as a white solid. The residue (213 mg) was purified again by column chromatography on silica gel (irregular SiOH 15-40 μm, 80 g, liquid injection with DCM, mobile phase: DCM/(MeOH (10% aq. NH₃)), gradient from 98:2 to 90:10 in 10 CV). The fractions containing the product were combined and evaporated to dryness to give a white solid. The residue (204 mg) was further purified by reverse phase (Stationary phase: X-Bridge-C18, 10 μm, 30×150 mm, mobile phase: 0.2% aq. NH₄HCO₃/MeOH, gradient from 60:40 to 0:100). The fraction of interest was evaporated, dissolved in 7 mL of a mixture of CH₃CN/water (1:4, v/v) and freeze-dried to give 113 mg of compound 140 (38% yield, white solid).

The compounds in the Table below were prepared by using an analogous method starting from the respective starting materials. The most relevant minor deviations to the referenced method are indicated as additional information in the column ‘Yield (%)’.

Compound number Structure Mass (mg) Yield (%) Compound 5

26 yellow solid 10 procedure with DCM/THF (5:2, v/v) From intermediate 21 Compound 19

81 22 procedure with DCM/THF (30:1, v/v) From intermediate 57 Compound 20

29 20 procedure with DCM/THF (30:1, v/v) From intermediate 59 Compound 23

73 32 procedure with DCM/THF (31:1, v/v) From intermediate 71 Compound 24

73 50 procedure with DCM/THF (28:1, v/v) From intermediate 73 Compound 25

149 67 procedure with DCM/THF (17:1, v/v) From intermediate 77 Compound 26

67 28 procedure with DCM/THF (17:1, v/v) From intermediate 81 Compound 27

149 55 procedure with DCM/THF (15:1, v/v) From intermediate 85 Compound 28

98 49 procedure with DCM/THF (19:1, v/v) From intermediate 89 Compound 29

107 46 procedure with DCM/THF (23:1, v/v) From intermediate 91 Compound 30

107 51 procedure with DCM/THF (28:1, v/v) From intermediate 95 Compound 37

53 40 procedure with DCM/THF (31:1, v/v) From intermediate 112 Compound 39

71 25 procedure with DCM/THF (29:1, v/v) From intermediate 121 Compound 55

84 37 procedure with DCM/TFA (3:1, v/v) From intermediate 185 Compound 56

87 38 procedure with DCM/TFA (3:1, v/v) From intermediate 185 Compound 57

126 pale yellow fluffy solid 36 procedure with DCM/TFA (5:2, v/v) From intermediate 190 Compound 58

17 pale yellow fluffy solid 13 procedure with DCM/TFA (5:2, v/v) From intermediate 194 Compound 60

176 pink solid 55 procedure with DCM/TFA (5:1, v/v) From intermediate 201 Compound 61

138 68 procedure with DCM/TFA (7:1, v/v) From intermediate 205 Compound 62

139 56 procedure with DCM/TFA (7:1, v/v) From intermediate 209 Compound 63

33 25 procedure with DCM/TFA (7:1, v/v) From intermediate 213 Compound 64

113 58 procedure with DCM/TFA (6:1, v/v) From intermediate 217 Compound 67

238 yellow fluffy solid 50 procedure with DCM/TFA (10:1, v/v) From intermediate 228 Compound 139

22 white solid 66 procedure with DCM/TFA (10:1, v/v) From intermediate 426 Compound 141

148 white solid 60 procedure with DCM/TFA (11:1, v/v) From intermediate 434 Compound 143

118 white solid 33 procedure with DCM/TFA (10:1, v/v) From intermediate 440 Compound 145

201 59 procedure with 22 eq. TFA From intermediate 390

Example B3 Preparation of Compound 3

A mixture of intermediate 14 (420.00 mg, 0.78 mmol) and TBAF (1M in THF) (0.86 mL, 0.86 mmol) in Me-THF (13 mL) was stirred at rt for 2 h. The resulting mixture was directly purified (without evaporation) by column chromatography on silica gel (irregular SiOH 15-40 μm, 24 g, liquid injection, mobile phase: DCM/MeOH/(10% aq. NH₃), gradient from 100:0 to 80:20). The fractions containing the product were evaporated to dryness to give a brown solid. Then, the solid was recrystallized from EtOH, filtered on a glass frit and washed with EtOH. The solid was collected to give an off-white solid. This solid and its filtrate were combined. The resulting residue (280 mg, off-white solid) was taken up with a mixture of DMSO/MeOH (50:50). The mixture was filtered to give fraction A (98 mg) as an off-white solid. The filtrate was purified by RP-HPLC (Stationary phase: X-Bridge-C18 5 μm 30×150 mm, mobile phase: aq. NH₄HCO₃ (0.5%)/CH₃CN, gradient from 65% aq. NH₄HCO₃ (0.5%), 35% CH₃CN to 25% aq. NH₄HCO₃ (0.5%), 75% CH₃CN). The fractions containing the product were combined and concentrated to dryness to give fraction B (86 mg) as an off-white solid. Fractions A and B (98 mg and 86 mg) were combined, diluted with a mixture of CH₃CN/EtOH (50:50) and sonicated for 15 min. The mixture was then concentrated under reduced pressure to give a solid. This solid was recrystallized from EtOH, filtered on a glass frit, washed once with EtOH and twice with Et₂O. The solid was collected, dried at 50° C. for 16 h to give 112 mg of an off-white solid which was recrystallized from EtOH, directly hot-filtered on a glass frit, washed once with EtOH and twice with Et₂O. The solid was collected and dried at 50° C. for 16 h to give 90 mg of compound 3 (27% yield, off-white solid). MP: 254° C. (DSC)

Preparation of Compound 4

A mixture of intermediate 18 (480.00 mg, 0.92 mmol) and TBAF (1M in THF) (1.00 mL, 1.00 mmol) in THF (10 mL) was stirred at rt for 1 h. The reaction mixture was directly purified by column chromatography on silica gel (irregular SiOH 15-40 μm, 120 g, liquid injection in a mixture of THF/DCM, mobile phase: DCM/MeOH (10% aq NH₃), gradient from 100:0 to 90:10 in 15 CV). The fractions containing the product were combined and evaporated to dryness to give a white solid. The residue (144 mg) was dissolved in EtOH then evaporated in vacuo (3 times) and dried at 50° C. in vacuo to give 138 mg of compound 4 (37% yield, white solid).

M.P.=280° C. (DSC).

Preparation of Compound 33

TBAF (1M in THF) (5.04 mL, 5.04 mmol) was added to a solution of intermediate 103 (3.03 g, 4.20 mmol, 75% purity based on LC/MS) in Me-THF (97 mL) and the reaction mixture was stirred at rt for 4 h. The reaction mixture was partitioned between EtOAc and a 10% aqueous solution of K₂CO₃. The organic layer was separated, dried over MgSO₄, filtered and evaporated to dryness. The residue (4.15 g) was purified by column chromatography on silica gel (Stationary phase: irregular bare silica 80 g, mobile phase: 0.2% NH₄OH, 98% DCM, 2% MeOH to 1% NH₄OH, 90% DCM, 10% MeOH). The fractions containing the product were mixed and concentrated to afford two batches (batch 1: 1.75 g and batch 2: 1.15 g). Batch 1 was purified again by column chromatography on silica gel (Stationary phase: irregular bare silica 80 g, mobile phase: 0.2% NH₄OH, 98% DCM, 2% MeOH to 1% NH₄OH, 90% DCM, 10% MeOH). The fractions containing the product were mixed and concentrated. The residue (894 mg) was taken up with a mixture of EtOH/Et₂O and the precipitate was filtered and dried to afford 838 mg of compound 33 (46% yield, Fraction A). M.P.=118° C. (DSC).

Batch 2 was purified again by column chromatography on silica gel (Stationary phase: irregular bare silica 80 g, mobile phase: 0.2% NH₄OH, 98% DCM, 2% MeOH to 1% NH₄OH, 90% DCM, 10% MeOH). The fractions containing the product were mixed and concentrated. The residue (536 mg) was taken up with a mixture of EtOH/Et₂O. The precipitate was filtered and dried to afford 330 mg of compound 33 (18% yield, Fraction B). Then, the fractions A and B were mixed, taken up with Et₂O and stirred for 30 min. The precipitate was filtered to give 841 mg of compound 33 (46% yield, white solid). The filtrate was combined to the one coming from the filtration of batch 2 and concentrated. The residue (374 mg) was taken up with Et₂O and purified by achiral SFC (Stationary phase: NH₂, 5 μm, 150×30 mm, mobile phase: 75% CO₂, 25% MeOH (0.3% iPrNH₂)). The fractions containing the product were mixed and concentrated. The residue (287 mg) was mixed with another batch (224 mg coming from a reaction performed on 1.11 g of intermediate 103), taken up with Et₂O. The filtrate was filtered and dried to afford additional 468 mg of compound 33.

Preparation of Compound 50

A mixture of intermediate 162 (2.00 g, 3.91 mmol) and TBAF (1M in THF) (8.01 mL, 8.01 mmol) in Me-THF (40 mL) was stirred at rt for 3 h. The reaction mixture was diluted with EtOAc washed with a solution 10% of K₂CO₃, twice with water and twice with a solution of saturated NaCl. The organic layer was decanted, dried over MgSO₄, filtered and evaporated to dryness. The residue was taken up several times with EtOH and evaporated to dryness. The residue was sonicated in CH₃CN, and the precipitate was filtered and dried to give 1.41 g of compound 50 (89% yield). M. P.=247° C. (DSC).

Preparation of Compound 93

To a solution of intermediate 319 (227.00 mg, 0.42 mmol) in Me-THF (4 mL), TBAF (1M in THF) was added (450.00 μL, 0.45 mmol). The solution was stirred at rt for 18 h then TBAF (1M in THF) (210.00 μL, 0.21 mmol) was added. The solution was stirred for 4 h then evaporated in vacuo to give an orange oil. The residue (434 mg) was purified by column chromatography on silica gel (Irregular SiOH 15-40 μm, 24 g, dry loading on Celite®, mobile phase: DCM/MeOH, gradient from 100:0 to 90:10). The fractions containing the product were combined and evaporated to dryness to give a white solid. The residue (148 mg) was suspended in DCM, the solid was filtered on a glass frit and dried in vacuo to give 102 mg of compound 93 as an off-white solid (57% yield). M.P.=165 (DSC).

The compounds in the Table below were prepared by using an analogous method starting from the respective starting materials. The most relevant minor deviations to the referenced method are indicated as additional information in the column ‘Yield (%)’.

Compound Mass number Structure (mg) Yield (%) Compound 9

252 71 procedure with DCM as solvent with 3 equiv. of TBAF From Intermediate 27 Compound 11

114 80 procedure with 2 equiv. of TBAF From Intermediate 31 Compound 12

83 72 procedure with 2 equiv. of TBAF From Intermediate 34 Compound 13

47 43 procedure with 2 equiv. of TBAF From Intermediate 40 Compound 14

200 off-white 93 From Intermediate 42 Compound 15

70 yellow solid 39 procedure with 2 equiv. of TBAF From Intermediate 46 Compound 16

57 51 procedure with 2 equiv. of TBAF From Intermediate 48 Compound 17

127 86 procedure with 2 equiv. of TBAF From Intermediate 51 Compound 18

42 46 procedure with 2 equiv. of TBAF From Intermediate 53 Compound 32

139 off-white powder 48 From Intermediate 99 Compound 36

88 40 procedure with 1.4 equiv. of TBAF From Intermediate 110 Compound 38

92 45 From Intermediate 117 Compound 44

125 pale yellow solid 80 From intermediate 141 Compound 48

154 pale yellow solid 73 From intermediate 157 Compound 49

126 white solid 72 From intermediate 161 Compound 53

145 51 From intermediate 177 Compound 54

155 off-white solid 70 From intermediate 181 Compound 68

208 off-white solid 64 From intermediate 232 Compound 69

215 pale yellow solid 64 From intermediate 236 Compound 72

383 yellow solid 94 From intermediate 249 Compound 73

291 off-white powder 63 From intermediate 252 Compound 74

245 79 From intermediate 255 Compound 75

25 34 From intermediate 258 Compound 76

55 42 From intermediate 261 Compound 77

93 50 From intermediate 264 Compound 78

19 26 From intermediate 267 Compound 80

110 white fluffy solid 49 From intermediate 274 Compound 81

186 white solid 63 From intermediate 279 Compound 84

5.3 orange gum 18 From intermediate 285 Compound 85

14 14 From intermediate 288 Compound 86

135 white solid 57 procedure with 1.7 equiv. of TBAF From intermediate 292 Compound 87

210 yellow solid 93 From intermediate 298 Compound 88

142 yellow solid 62 From intermediate 301 Compound 89

103 yellow solid 92 From intermediate 304 Compound 90

72 yellow powder 50 From intermediate 308 Compound 91

254 72 From intermediate 314 Compound 96

240 white solid 66 procedure with 2 equiv. of TBAF From intermediate 330 Compound 126

34 19 procedure with 2.2 equiv. of TBAF From intermediate 398 Compound 127

83 off-white solid 49 From intermediate 399 Compound 128

120 orange solid 59 procedure with 2.2 equiv. of TBAF From intermediate 400 Compound 129

102 white solid 59 From intermediate 402 Compound 130

48 off-white solid 28 From intermediate 404 Compound 131

77 off-white solid 20 From intermediate 406 Compound 132

62 white solid 57 From intermediate 408 Compound 133

228 off-white solid 59 From intermediate 410 Compound 134

58 off-white solid 29 From intermediate 412 Compound 135

19 off-white solid 6 •CF₃COOH From intermediate 414 Compound 136

197 white solid 78 From intermediate 418 Compound 137

133 off-white solid 42 From intermediate 422 Compound 138

98 off-white solid 33 From intermediate 422 Compound 142

47 white solid 67 From intermediate 438 Compound 144

98 white fluffy solid 65 From intermediate 444 Compound 146

81 79 From intermediate 470 Compound 147

57 white solid 71 From intermediate 473 Compound 148

47 white solid 63 From intermediate 449 Compound 149

108 yellow solid 81 From intermediate 451 Compound 150

173 70 From intermediate 477 Compound 151

165 53 From intermediate 465 Compound 152

140 yellow solid 61 From intermediate 467 Compound 153

115 Yellow solid 79 TRANS A (SS or RR) From intermediate 456 Compound 154

52 White solid 71 TRANS B (RR or SS) From intermediate 458 Compound 155

155 38 4 h TRANS mixture (RR or SS) From intermediate 568 Compound 156

78 83 From intermediate 479 Compound 157

73 40 From intermediate 502 Compound 158

238 White solid 95 Procedure: reaction time 20 min From intermediate 562 Compound 159

138 40 Procedure: reaction time 1 h 30 From intermediate 492 Compound 160

240 50 Procedure: reaction time 2 h From intermediate 494 Compound 161

224 56 procedure with 1.5 equiv of TBAF THF 4 h From intermediate 518 Compound 162

7 90 procedure with 2 equiv of TBAF Me-THF 2 h From intermediate 539 Compound 163

64 22 procedure with 1.1 equiv of TBAF Me-THF 17 h From intermediate 520 Compound 164

112 50 procedure with 1.5 equiv of TBAF THF O/N From intermediate 506 Compound 165

94 40 procedure with 1.5 equiv of TBAF THF 2 h From intermediate 530 Compound 166

21 10 procedure with 1.1 equiv of TBAF Me-THF o/n From intermediate 536 Compound 167

92 64 procedure with 2 equiv of TBAF Me-THF 2 h From intermediate 540 Compound 168

172 76 procedure with 1.5 equiv of TBAF THF 2 h 30 From Intermediate 509 Compound 169

790 77 procedure with 2 equiv of TBAF Me-THF 3 h From intermediate 534 Compound 170

88 71 procedure with 3 equiv of TBAF Me-THF 4 h From intermediate 532 Compound 182

42 68 procedure with 2 equiv of TBAF Me-THF 3 h From intermediate 586 Compound 183

60 27 procedure with 6 equiv of TBAF (TBAF on silica gel 1.55 mmol/g) Me-THF 18 h From intermediate 588

Example B4 Preparation of Compound 6

HCl (3M in H₂O) (1.88 mL, 5.64 mmol) was added to a solution of intermediate 22 (340.00 mg, 0.56 mmol) in MeOH (8.64 mL) and the reaction mixture was stirred overnight at rt. The following day, just the TBDMS was cleaved so the reaction was put at 65° C. for 4 h. After 4 h, the reaction was almost finished but there was still some NBoc product so the reaction was put at rt over the weekend. The reaction mixture was cooled to rt, poured onto a 10% aqueous solution of K₂CO₃ and extracted with DCM. The organic layer was decanted, dried over MgSO₄, filtered and evaporated to dryness.

The residue (183 mg, yellow powder) was gathered with another batch (from 110 mg of intermediate 22) and purified via achiral SFC (Stationary phase: CYANO 6 μm 150×21.2 mm, mobile phase: 80% CO₂, 20% MeOH (0.3% iPrNH₂)). The fractions containing the product were evaporated to give 139 mg of a white powder. This solid was taken up in Et₂O to provide 105 mg of compound 6 (48% yield, white solid). MP: 241° C. (K)

The compounds in the Table below were prepared by using an analogous method starting from the respective starting materials.

Compound Mass Yield number Structure (mg) (%) Compound 7

135 white powder 40

Example B5 Preparation of Compound 21

TBAF (on silica gel 1.5 mmol/g) (1.43 g, 2.15 mmol) was added to a solution of intermediate 63 (218.00 mg, 0.36 mmol) in Me-THF (10 mL) and the reaction mixture was stirred at rt for 18 h. The reaction mixture was diluted with DCM, filtered through paper and poured onto a 10% aqueous solution of K₂CO₃. The organic layer was decanted, washed with water, dried over MgSO₄, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel (irregular SiOH, 24 g, mobile phase: heptane/MeOH/EtOAc, gradient from 2% MeOH, 40% EtOAc, 60% heptane to 2% MeOH, 60% EtOAc, 40% heptane). The pure fractions were collected and evaporated to dryness. The residue was crystallized from Et₂O, filtered and dried to give 77 mg of compound 21 (43% yield).

Preparation of Compound 33

TBAF (on silica gel 1.5 mmol/g) (2.30 g, 3.46 mmol) was added to a solution of intermediate 103 (315.00 mg, 0.58 mmol) in Me-THF (14 mL) and the reaction mixture was stirred at rt for 18 h. The reaction mixture was diluted with EtOAc and poured onto a 10% aqueous solution of K₂CO₃. The organic layer was decanted, washed with brine, dried over MgSO₄, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel (irregular SiOH, 24 g, mobile phase: DCM/MeOH, gradient from 100:0 to 90:10). The pure fractions were collected and evaporated to dryness. The residue was crystallized from EtOH/Et₂O then the precipitate was filtered and dried to give 128 mg of compound 33 (51% yield). M.P.=153° C. (DSC).

The compounds in the Table below were prepared by using an analogous method starting from the respective starting materials. The most relevant minor deviations to the referenced method are indicated as additional information in the column ‘Yield (%)’.

Mass Yield Compound Structure (mg) (%) Compound 22

 66 30 Compound 31

 79 43 Procedure with 3 equiv of TBAF Compound 34

126 47 Compound 35

 98 52 Compound 40

 55 32 Compound 42

158 58 Compound 43

 88 31 Compound 45

 28 24 Compound 46

 65 39 Procedure with 9 equiv. of TBAF Compound 47

 37 28 Compound 51

 37 28 Compound 52

 42 8 Compound 66

102 37 Procedure with 4 equiv. of TBAF Compound 171

 70 80 Compound 172

 14 17 procedure with 1.5 equiv. of TBAF Compound 173

159 42 Compound 174

167 32 Compound 175

 8 21 Compound 176

 56 68 Procedure with 1.5 equiv. of TBAF Compound 177

186 54 procedure with 1.1 equiv. of TBAF

Example B6 Preparation of Compound 97

TFA (2 mL) was added to a solution of intermediate 335 (89.78 mg, 0.19 mmol) in DCM (5 mL) and the mixture was stirred for 3 h at rt. The reaction mixture was concentrated in vacuo and purified by column chromatography on silica gel (24 g Si-PPC, mobile phase: DCM/2 M ammonia in MeOH, gradient from 0% to 10% of MeOH) to give a yellow oil. The residue (110 mg) was further purified by prep-HPLC (Waters X-bridge, 19×250 mm, C₁₈ column, mobile phase: 0.1% NH₄OH/CH₃CN, from 10% to 98% of CH₃CN) and freeze-dried to give 20 mg of the desired compound (28% yield, white solid).

The compounds in the Table below were prepared by using an analogous method starting from the respective starting materials. The most relevant minor deviations to the referenced method are indicated as additional information in the column ‘Yield (%)’.

Compound Mass Yield number Structure (mg) (%) Compound 98

25 off-white solid 20 Procedure with DCM/TFA (1:1, v/v) Compound 99

60 off-white solid 43 Procedure with DCM/TFA (1:1, v/v) Compound 125

104 40 Procedure with DCM/TFA (3:1, v/v)

Example B7 Preparation of Compound 101

A mixture of intermediate 345 (248.00 mg, 0.48 mmol) and TBAF (1M in THF) (0.68 mL, 0.68 mmol) in THF (5.5 mL) was stirred at rt for 18 h. The reaction mixture was directly (without evaporation) purified by column chromatography on silica gel (irregular SiOH 15-40 μm, 120 g, mobile phase: DCM/MeOH, gradient from: 100:0 to 95:5). The pure fractions were mixed and the solvent was evaporated. The residue was taken up by Et₂O, filtered and dried to give 0.127 g of compound 101 (66% yield).

Preparation of Compound 103

A mixture of intermediate 350 (213.00 mg, 0.41 mmol) and TBAF (1M in THF) (0.59 mL, 0.59 mmol) in THF (4.7 mL) was stirred at rt for 18 h. The reaction mixture was directly purified by column chromatography on silica gel (irregular SiOH 15-40 μm, 120 g, mobile phase: DCM/MeOH, gradient from 100:0 to 95:5). The pure fractions were mixed and the solvent was evaporated. The residue was taken up by Et₂O, filtered and dried to give 109 mg of compound 103 (66% yield).

Preparation of Compound 124

A mixture of intermediate 396 (50.00 mg, 93.00 μmol) and TBAF (1M in THF) (0.10 mL, 0.10 mmol) in THF (1 mL) was stirred at rt for 18 h. The reaction mixture was directly (without evaporation) purified by column chromatography on silica gel (irregular SiOH 15-40 μm, 40 g, liquid injection (THF/DCM), mobile phase gradient: DCM/MeOH (10% aq NH₃) from 100:0 to 90:10 in 15 CV). The fractions containing the product were combined and evaporated to dryness to give 31 mg of compound 124 (79% yield, off-white solid).

The compounds in the Table below were prepared by using an analogous method starting from the respective starting materials.

Compound Mass Yield number Structure (mg) (%) Compound 102

25  36 Compound 104

68  40 Compound 178

190 (70% purity based on LC/MS) 100 procedure with 1.1 equiv. of TBAF

Example B8 Preparation of Compound 105

TBAF (on silica gel 1.5 mmol/g) (1.77 g, 2.65 mmol) was added to a solution of intermediate 354 (276.00 mg, 0.44 mmol) in Me-THF (12 mL) and the reaction mixture was stirred at rt for 18 h. The reaction mixture was diluted with DCM, filtered through paper and poured onto a 10% aqueous solution of K₂CO₃. The organic layer was decanted, washed with water, dried over MgSO₄, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel (irregular SiOH, 24 g, mobile phase: heptane/MeOH/EtOAc, gradient from 2% MeOH, 40% EtOAc, 60% heptane to 2% MeOH, 60% EtOAc, 40% heptane). The pure fractions were collected and evaporated to dryness. The residue was crystallized from Et₂O, filtered and dried to give 103 mg of compound 105 (42% yield).

The compounds in the Table below were prepared by using an analogous method starting from the respective starting materials.

Compound Mass Yield number Structure (mg) (%) Compound 106

107 42 Compound 107

117 59

Example B9 Preparation of Compound 108

TFA (0.213 mL) was added at 5° C. to a solution of intermediate 361 (93.00 mg, 0.18 mmol) in DCM (2.0 mL). The reaction mixture was stirred at 5° C. for 1 h and 30 min. The crude was diluted with DCM and poured onto a 10% aqueous solution of K₂CO₃, dried over MgSO₄, filtered and evaporated to dryness to provide a yellow powder. The residue (120 mg) was purified by column chromatography on silica gel (deposit solid, irregular SiOH, 30 g, mobile phase: DCM/MeOH, gradient from 100:0 to 90:10). The pure fractions were collected and evaporated to dryness to give 18 mg of a white powder. The product was taken up with Et₂O to give 10 mg of compound 108 (13% yield, white powder).

Preparation of Compound 115

TFA (772 μL) was added at 5° C. to a solution of intermediate 371 (457.00 mg, 0.67 mmol) in DCM (7.31 mL). The reaction mixture was stirred at rt overnight. The reaction was not completed. Additional TFA (360 μL) was added at 5° C. The crude mixture was diluted with DCM and poured onto a 10% aqueous solution of K₂CO₃, dried over MgSO₄, filtered and evaporated to dryness to provide an orange powder. The residue (500 mg) was combined with another batch (100 mg coming from a reaction performed on 79 mg of intermediate 371) and purified by column chromatography on silica gel (irregular SiOH, 40 g, mobile phase: DCM/MeOH/NH₄OH, gradient from 100% DCM to 92% DCM 8% MeOH, 0.8% NH₄OH). The fractions containing the product were collected and evaporated to dryness to give a light orange powder. The residue (240 mg) was purified by reverse phase (Stationary phase: X-Bridge-C18, 5 μm, 30×150 mm, mobile phase: NH₄CO₃ (0.2%)/MeOH, gradient from 60:40 to 20:80). The fractions containing the product were combined and concentrated to provide a yellow powder. The resulting residue (78 mg) was purified again by reverse phase (Stationary phase: X-Bridge-C18, 5 μm, 30×150 mm, mobile phase: HCOONH₄ (0.6 g/L, pH=3.5)/CH₃CN, gradient from 75:25 to 35:65). The fractions containing the product were combined and concentrated to provide a light yellow powder. The residue (64 mg) was taken up with Et₂O to provide 51 mg of a yellow powder as a formiate salt. So, the residue was diluted with DCM and poured twice onto water and NaCl, dried over MgSO₄, filtered and evaporated to dryness to give a white powder. The residue (42 mg) was taken up with Et₂O to provide 38 mg of compound 115 (13% yield, white powder). M.P.=203° C.

The compounds in the Table below were prepared by using an analogous method starting from the respective starting materials. The most relevant minor deviations to the referenced method are indicated as additional information in the column ‘Yield (%)’.

Compound Mass Yield number Structure (mg) (%) Compound 109

65 white powder 34 Compound 110

71 white powder 39 Procedure with DCM/TFA (11:1, v/v) Compound 111

77 white powder 88 Procedure with DCM/TFA (5:1, v/v) Compound 112

58 white powder 41 Compound 113

10 colorless oil 15 Compound 116

108 46 Procedure with DCM/TFA (18:1, v/v) Compound 117

174 52 Procedure with DCM/TFA (10:1, v/v) Compound 118

101 31 Procedure with DCM/TFA (10:1, v/v) Compound 119

155 53 Procedure with DCM/TFA (11:1, v/v) Compound 120

118 45 Procedure with DCM/TFA (10:1, v/v) Compound 121

141 43 Procedure with DCM/TFA (10:1, v/v) Compound 122

43 white powder 27 Procedure with DCM/TFA (6:1, v/v)

Example B10 Preparation of Compound 114

HCl (3M in H₂O) (0.78 mL, 2.33 mmol) was added to a solution of intermediate 369 (154.00 mg, 0.23 mmol) in MeOH (3.6 mL) and the reaction mixture was stirred several days at rt. The reaction mixture was cooled to rt, poured onto a 10% aqueous solution of K₂CO₃ and extracted with DCM. The organic layer was decanted, dried over MgSO₄, filtered and evaporated to dryness to provide an orange powder. The residue (300 mg) was purified by column chromatography on silica gel (Irregular SiOH, 25 g, solid deposit; mobile phaseNH₄OH/MeOH/DCM, gradient from 0% NH₄OH, 0% MeOH, 100% DCM to 0.5% NH₄OH, 5% MeOH, 95% DCM). The fractions containing the product were collected and evaporated to dryness to give a colorless oil. The residue (30 mg) was further purified by reverse phase (Stationary phase: X-Bridge-C18 5 μm, 30×150 mm, mobile phase: NH₄CO₃ (0.2%)/CH₃CN, gradient from 65:35 to 25:75). The fractions containing the product were combined and concentrated to dryness. The residue (28 mg, yellow oil) was taken up with Et₂O to provide 27 mg of compound 114 (26% yield, yellow oil).

Example B11 Preparation of compound 179

A solution of intermediate 573 (200 mg; 0.34 mmol) and silica gel (203 mg; 3.39 mmol) in toluene (10.00 mL) was stirred at 110° C. for 16 h. The reaction was filtered. The filtrate was concentrated. The crude product was purified by preparative high-performance liquid chromatography over Waters Xbridge 150*25 5 u (Mobile phase: CH₃CN/H₂O (10 mM NH₄HCO₃-ACN v/v) Gradient from 35:65 to 65:35, v/v). The pure fractions were collected and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to give 40 mg of compound 179 (24% yield) as a white solid.

Example B12

Preparation of Compound 180

To a stirred solution of intermediate 179 in toluene (10.00 mL) was added silica gel (0.13 g, 2.20 mmol) at rt. The reaction mixture was stirred at 100-105° C. for 16 h. The reaction was concentrated. The crude was purified by preparative high-performance liquid chromatography over Phenomenex Synergi C18 150*25*10 um (Mobile phase: CH₃CN/H₂O (10 mM NH₄HCO₃-ACN v/v) Gradient from 29% to 64%, v/v). The pure fractions were collected and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to give 20 mg of compound 180 (18% yield) as a yellow solid.

Example B13 Preparation of Compound 181

A mixture of intermediate 581 (300 mg; 0.41 mmol) in DCM (3.00 mL) was added TFA (34 μL; 0.45 mmol). The reaction mixture was stirred at rt for 1 hour. The mixture was evaporated to give 300 mg of crude material as a yellow solid. This material was combined with the crude from a parallel reaction. The combined crude product was purified by preparative high-performance liquid chromatography over Column: Kromasil 150*25 mm*10 um. Mobile phase: Water (0.05% ammonia hydroxide v/v)/ACN, Gradient from 65/35 to 35/65). Gradient Time(min) 8; 100% B Hold Time(min) 2; Flow Rate (ml/min) 30. The pure fractions were collected and the volatiles were reduced under vacuum. The remaining aqueous layer was freeze-dried to give 120 mg of compound 181 (75% yield) as a yellow solid.

Example B14 Preparation of compound 1i

TBAF (1M in THF) (775.07 μL, 0.77 mmol) was added to a solution of intermediate 13i (234.00 g, 0.39 mmol) in Me-THF and the reaction mixture was stirred at rt for 3 h. A 10% aqueous solution of K₂CO₃ and EtOAc were added. The organic layer was decanted, washed with water then brine, dried over MgSO₄, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel (irregular SiOH, 25 g, mobile phase: gradient from 0.5% NH₄OH, 5% MeOH, 95% DCM to 1% NH₄OH, 10% MeOH, 90% DCM). The pure fractions were collected and evaporated to dryness. The residue was taken up with Et₂O and the solid was filtered and dried to give 121 mg of compound 1i (64% yield). M.P.=149° C. (K).

Preparation of Compound 4i

To a solution of intermediate 23i (127.00 mg, 0.17 mmol) in Me-THF (1.85 mL), TBAF (1M in THF) (0.18 mL, 0.18 mmol) was added and the mixture was stirred at rt overnight. The mixture was evaporated under vacuum to give a yellow gum. The residue was purified by column chromatography on silica gel (irregular SiOH, 15-40 μm, 4 g, dry loading on Celite®, mobile phase: DCM/MeOH, gradient from 99:1 to 94:6). The fractions containing the product were combined and concentrated under vacuum to give 69 mg of compound 4i (85% yield, white solid).

Preparation of Compound 7i

To a solution of intermediate 35i (460.00 mg, 0.75 mmol) in Me-THF (8.2 mL), TBAF (1M in THF) (0.82 mL, 0.82 mmol) was added and the mixture was stirred at rt for 4 h. The mixture was evaporated in vacuo. The residue (714 mg, orange foam) was purified by column chromatography on silica gel (irregular SiOH, 15-40 μm, 40 g, liquid loading with DCM, mobile phase: DCM/MeOH, gradient from 99:1 to 94:6). The fractions containing the product were combined and evaporated to dryness. The residue (319 mg, white solid) was dried under vacuum (50° C., 16 h) to give 280 mg of compound 7i (75% yield, white solid).

Preparation of Compound 13i

A mixture of intermediate 54i (390.00 mg, 0.73 mmol) and TBAF (1M in THF) (0.77 mL, 0.77 mmol) in Me-THF (12 mL) was stirred at rt for 20 h. The residue was directly purified by column chromatography on silica gel (irregular SiOH 15-40 μm, 24 g, dry load on Celite®, mobile phase: DCM/MeOH (+10% aq. NH₃), gradient from 98:2 to 85:15). The fractions containing the product were combined and evaporated to dryness. The residue (120 mg, brown solid) was recrystallized from EtOH, filtered on a glass frit and washed once with EtOH. The solid was collected and was dried at 50° C. under reduced pressure for 16 h to give 94 mg of compound 13i (31% yield, off-white solid).

Preparation of compounds 22i and 23i

To a solution of intermediate 68i (491 mg, 0.78 mmol) in Me-THF (9 mL) was added TBAF (1M in THF) (0.86 mL, 0.86 mmol) and the mixture was stirred at rt overnight. The mixture was evaporated in vacuo. The residue was purified by preparative LC (irregular SiOH, 15-40 μm, 80 g, Grace, mobile phase gradient: from DCM/MeOH: 100/0 to 88/12). The pure fractions were mixed and the solvent was evaporated. The residue was crystallized from MeCN and aceton, filtered and dried, yielding: 0.256 g of compound 18i (64%).

0.2 g of compound 18i was purified via chiral SFC (stationary phase: Chiralcel OJ-H 5 μm 250×20 mm, mobile phase: 75% CO₂, 25% EtOH (0.3% iPrNH₂)). The pure fractions were evaporated, taken up by Et₂O, filtered and dried, yielding: 54 mg of compound 22i (13%) and 45 mg of compound 23i (11%).

The compounds in the Table below were prepared by using an analogous method starting from the respective starting materials. The most relevant minor deviations to the referenced method are indicated as additional information in the column ‘Yield (%)’.

Compound Mass Yield number Structure (mg) (%) Compound 2i

56 63 procedure with 2 equiv. of TBAF Compound 3i

317 66 procedure with 1.1 equiv. of TBAF Compound 5i

220 pale yellow solid 64 procedure with 1.1 equiv of TBAF Compound 6i

275 pale yellow solid 74 procedure with 1.1 equiv of TBAF Compound 8i

60 60 procedure with 1.4 equiv of TBAF Compound 10i

87 beige solid 50 procedure with 1.1 equiv of TBAF Compound 11i

15 26 procedure with 1.1 equiv of TBAF Compound 12i

129 white solid 52 procedure with 1.1 equiv of TBAF Compound 14i

136 beige solid 55 procedure with 1.1 equiv of TBAF Compound 15i

46 brown solid 24 procedure with 1.1 equiv of TBAF Compound 16i

87 51 procedure with 3 equiv of TBAF Compound 17i

37 48 procedure with 2 equiv of TBAF Compound 18i

256 64 procedure with 1.1 equiv of TBAF Compound 19i

73 46 procedure with 3 equiv of TBAF Compound 20i

94 57 procedure with 3 equiv of TBAF Compound 21i

74 18 procedure with 1.2 equiv of TBAF Compound 25i

80 39.5 procedure with 2.8 equiv of TBAF Compound 26i

74 45 procedure with 2 equiv of TBAF Compound 29i

308 92 procedure with 2 equiv of TBAF Compound 30i

65 48 procedure with 1.6 equiv of TBAF in THF

Example B15 Preparation of Compound 9i

A mixture of intermediate 38i (565.0 mg 1.12 mmol) in dry DCM (stabilized with amylene) (19 mL) was treated with TFA (1.64 mL, 21.40 mmol) and stirred at rt for 30 min. The mixture was poured into a saturated aqueous solution of NaHCO₃, extracted with a mixture of DCM/MeOH (90:10, 6×100 mL). The combined organic layers were dried over MgSO₄ and filtered. Some Celite® was added and the resulting mixture was evaporated under vacuum to afford a dry load. The residue was purified by column chromatography on silica gel (irregular silica, 30 μm, 80 g, dry loading, mobile phase: DCM/MeOH, gradient from 100:0 to 95:5 in 20 CV). The fractions containing the product were combined and evaporated to dryness to afford an off-white solid. The residue was partially recrystallized from EtOH (250 mL of refluxing EtOH which did not allowed complete solubilization, no more EtOH was added). After allowing the suspension to slowly cool down to rt, the resulting solid was filtered and dried at 50° C. under high vacuum for 4 h. The residue (178 mg, white solid) was further dried at 50° C. under high vacuum for 24 h to afford 177 mg of compound 9i (39% yield, white solid).

Example B16 Preparation of Compound 24i (Cis Stereochemistry in Dimethyl Morpholine)

A mixture of compound 2i (0.162 g; 0.306 mmol), isobutyric acid (0.0685 mL; 9.5 mmol), HATU (0.291 g; 0.765 mmol), DIPEA (0.264 mL; 1.53 mmol) in DCM (3 mL) was stirred at room temperature for 18 hours. The solution was poured onto water and extracted with DCM. The organic layer was washed with H₂O, then brine, dried over MgSO₄, filtered and evaporated to dryness. The residue was purified by chromatography over silica gel (irregular SiOH, 60 g; mobile phase: DCM/MeOH: 100/0 to 97/3). The pure fractions were collected and evaporated to dryness yielding 0.208 g. This fraction was purified by chromatography via Reverse phase (stationary phase: YMC-actus Triart-C18 10 μm 30*150 mm, mobile phase: gradient from 60% NH₄HCO₂ 0.2%, 40% ACN to 0% NH₄HCO₂ 0.2%, 100% ACN). The pure fractions were collected and evaporated to dryness, yielding: 0.088 g of compound 24i (48%).

Example B17 Preparation of Compound 27i

A suspension of intermediate 92i (133.9 mg, 0.48 mmol), intermediate 12i (120 mg, 0.531 mmol), Pd(OAc)₂ (10.9 mg, 0.048 mmol), BINAP (30 mg, 0.048 mmol) and Cs₂CO₃ (394 mg, 1.2 mmol) in 1,4-dioxane (3.9 mL) was purged with N₂ and stirred at 120° C. for 3 h. The reaction mixture was cooled to room temperature, poured onto ice-water and extracted with EtOAc. The organic layer was decanted, washed with brine, dried over MgSO4, filtered over a pad of Celite® and evaporated to give 160 mg of brown oil. The was purified by chromatography over silica gel (Biotage, SNAP Ultra; 50 g; gradient: from 98% DCM, 2% MeOH, 0.2% NH₄OH to 95% DCM, 5% MeOH, 0.5% NH₄OH). The pure fractions were collected and the solvent was evaporated to give 96 mg of yellow oil. This fraction was purified by reverse phase (Stationary phase: YMC-actus Triart-C18 10 μm 30*150 mm, Mobile phase: Gradient from 55% NH₄HCO₂ 0.2%, 45% ACN to 0% NH₄HCO₂ 0.2%, 100% ACN). The pure fractions were collected and the solvent was evaporated to give 68 mg of yellow foam. This fraction was recrystallized from ACN. The precipitate was filtered and dried to give 62 mg of compound 27i as a yellow solid (27%). M.P.: 206° C. (Kofler). M.P.: 197° C. (DSC).

The compound in the Table below was prepared by using an analogous method starting from the respective starting materials. The most relevant minor deviations to the referenced method are indicated as additional information in the column ‘Yield (%)’.

Compound Mass Yield number Structure (mg) (%) Compound 28i

25 22

Example B18 Preparation of Compound 31i

To a solution of intermediate 109i (460.00 mg, 0.75 mmol) in Me-THF (8.2 mL), TBAF (1M in THF) (0.82 mL, 0.82 mmol) was added and the mixture was stirred at rt for 4 h.

The reaction mixture was directly (without evaporation) purified by preparative LC (irregular SiOH 15-40 μm, 120 g, mobile phase gradient: DCM/MeOH from 100/0 to 95/5). The fractions containing product were mixed and the solvent was evaporated. The residue was crystallized from acetone and Et₂O and dried to give 0.171 g.

This fraction was purified by chromatography over silica gel by reverse phase (stationary phase: X-Bridge-C18 5 μm 30*150 mm, mobile phase: gradient from 90% NH₄HCO₃ 0.2%, 10% ACN to 50% NH₄HCO₃ 0.2%, 50% ACN). The pure fractions were mixed and the solvent was evaporated.

The residue was suspended in Et₂O, filtered and dried to give 0.05 g of compound 31i (13% yield).

Analytical Part

LCMS (Liquid chromatography/Mass spectrometry)

The High Performance Liquid Chromatography (HPLC) measurement was performed using a LC pump, a diode-array (DAD) or a UV detector and a column as specified in the respective methods. If necessary, additional detectors were included (see table of methods below).

Flow from the column was brought to the Mass Spectrometer (MS) which was configured with an atmospheric pressure ion source. It is within the knowledge of the skilled person to set the tune parameters (e.g. scanning range, dwell time . . . ) in order to obtain ions allowing the identification of the compound's nominal monoisotopic molecular weight (MW). Data acquisition was performed with appropriate software.

Compounds are described by their experimental retention times (R_(t)) and ions. If not specified differently in the table of data, the reported molecular ion corresponds to the [M+H]⁺ (protonated molecule) and/or [M−H]⁻ (deprotonated molecule). In case the compound was not directly ionizable the type of adduct is specified (i.e. [M+NH₄]⁺, [M+HCOO]⁻, etc. . . . ). For molecules with multiple isotopic patterns (Br, Cl.), the reported value is the one obtained for the lowest isotope mass. All results were obtained with experimental uncertainties that are commonly associated with the method used.

Hereinafter, “SQD” means Single Quadrupole Detector, “RT” room temperature, “BEH” bridged ethylsiloxane/silica hybrid, “HSS” High Strength Silica, “DAD” Diode Array Detector.

TABLE LCMS Method codes (Flow expressed in mL/min; column temperature (T) in ° C.; Run time in minutes). Flow Method Mobile (mL/min) Run code Instrument Column phase gradient T (° C) time Method Waters: Acquity Waters: A: 95% 84.2% A for 0.343 6.2 1 UPLC ®- DAD BEH C18 CH₃COONH₄ 0.49 min, to 10.5% A 40 and Quattro (1.7 μm, 7 mM/5% CH₃CN, in 2.18 min, held for Micro ™ 2.1 × 100 mm) B: CH₃CN 1.94 min, back to 84.2% A in 0.73 min, held for 0.73 min. Method Waters: Waters: A: 95% From 84.2% A to 0.343 6.1 2 Acquity BEH C18 CH₃COONH₄ 10.5% A in 2.18 min, 40 UPLC ® H- (1.7 μm, 7 mM/5% CH₃CN, held for 1.94 min, Class - DAD 2.1 × 100 mm) B: CH₃CN back to 84.2% A in and SQD 2 0.73 min, held for 0.73 min. Method Waters: BEH ®- C18 A: 95% 95% A to 5% A in 1 0.5 3.3 3 Acquity (1.7 μm, CH₃COONH₄ min, held for 1.6 40 UPLC ® H- 2.1 × 100 mm) 7 mM/5% CH₃CN, min, back to 95% A Class - DAD B: CH₃CN in 1.2 min, held for and QDa 0.5 min. Method Waters: Luna - C18 A: 95% 95% A held 0.5 min, 2 5.5 4 ZMD (3 μm, Water then from 95% A to 40 quadripole - 30 × 4.6 mm) (with 0.1% 5% A 4.0 min, held Waters 1525 CH₃COOH), for 1.0 min. LC system B: CH₃CN with DAD (with 0.1% detector or CH₃COOH) Sedex 85 evaporative light scattering detector Method Waters: Acquity A: 95% 95% A held 0.4 min, 0.4 6.4 5 Micromass HST - C18 Water then from 95% A to 40 ZQ2000 - (1.8 μM, (with 0.1% 5% A 5.2 min, held Waters 2.1 × 100 mm) CH₃COOH), for 0.8 min. Acquity UPLC B: CH₃CN system (with 0.1% equipped with CH₃COOH) PDA detector Method Agilent 1100 YMC A: 0.1% From 95% A to 5% 2.6 6.0 6 series DAD ODS-AQ C18 HCOOH A in 4.8 min, held for 35 LC/MS (50 × 4.6 mm, in H₂O 1.0 min, to 90% A in G1956A 3.0 μm) B: CH₃CN 0.2 min. Method Agilent 1260 ACE C18 A: 100% 95% A to 0% A in 2.2 2 7 series equipped column Water 1.5 min 50 with DAD and (3 μM, (with 0.05% TFA), Agilent G6120B 3.0 × 50 mm) B: 100% detector CH₃CN Method Agilent 1200 Phenomenex A: H₂O 90% A held for 0.8 0.8 10 8 equip with Luna- C18, (0.1% TFA), min then 90% A to 50 MSD 6110 50 × 2 mm, B: CH₃CN 20% A in 3.7 min, 5 μm (0.05% TFA) held for 2 min, back to 90% A in 2 min, held for 0.5 min. Method Agilent 1200 XBridgc A: H₂O 100% A held for 1.00 0.8 10 9 equip with Shield RP18 (0.05% NH₃•H₂O), min, then from 100% 40 MSD 6110 (5 μm, B: CH₃CN A to 40% A in 4.00 2.1 × 50 mm) min, then from 40% A to 5% A in 2.50 min, back to 100% A in 2.00 min. Method Agilent: Agilent: A: CF₃COOH 100% A for 1 min, to 0.8 10.5 10 1100/1200 - TC-C18 0.1% in water, 40% A in 4 min, 50 DAD and (5 μm, B: CF₃COOH to 15% A in 2.5 min, MSD 2.1 × 50 mm) 0.05% in CH₃CN back to 100% A in 2 min. Method Agilent 1200 Phenomenex A: H₂O 100% A held for 1 0.8 10 11 equip with Luna- C18, (0.1% TFA, mn then 100% A to 50 MSD 6110 50 × 2 mm, B: CH₃CN 40% A in 4 mn 5 μm (0.05% TFA) then 40% A to 15% A in 2.5 mn then back to 100% A in 2 mn held for 0.5 min. Melting Point (DSC, K, MP50 or WRS-2A)

For a number of compounds, melting points (MP) were determined with a DSCl (Mettler-Toledo). Melting points were measured with a temperature gradient of 10° C./minute. Maximum temperature was 350° C. Values are peak values. Indicated in the table as DSC.

For a number of compounds, melting points were obtained with a Kofler hot bench (indicated with (K) in the analytical table), consisting of a heated plate with linear temperature gradient, a sliding pointer and a temperature scale in degrees Celsius.

For a number of compounds, melting points were obtained with an automatic Melting Point Apparatus WRS-2A (indicated with WRS-2A in the analytical table). Melting points were measured with a temperature gradient of 5° C. per minute starting from room temperature to a maximum value of 320° C.

For a number of compounds, melting points were obtained with a Mettler Toledo MP50 apparatus (indicated with MP50 in the analytical table). Melting points were measured with a temperature gradient of 10° C. per minute starting from 50° C. (waiting time 10 second) to a maximum value of 300° C.

In the Table below, ‘N^(o)’ means compound number.

MP N^(o) MP (° C.) method Rt [M + H]⁺ LCMS Method  1 — — 4.17 389 4  2 230 K 2.75 496 2  3 254 DSC 3.18 423 1  4 280 DSC 2.59 407 1 277 DSC  5 261 DSC 3.07 427 1  6 241 K 2.75 389 1  7 245 K 2.75 389 1  9 238 K 2.45 431 1  10 231 K 2.75 496 2  11 236 K 3.04 496 1  12 120 (gum) K 2.65 462 1  13 125 (gum) K 3.34 524 1  14 266 DSC 3.18 423 1  15 — — 2.64 506 1  16 248 K 2.93 403 1  17 248 K 2.73 392 1  18 140 K 3.13 417 1  19 154 K 2.95 461 1  20 >260  K 2.30 389 1  21 170 DSC 3.37 495 1  22 — — 3.17 493 1  23 213 DSC 2.73 459 1  24 145 K 2.11 389 1  25 213 DSC 2.73 459 1  26 155 DSC 2.82 459 1  27 149 DSC 2.80 459 1  28 194 DSC 2.62 445 1  29 135 DSC 3.09 418 1  30 195 DSC 3.51 451 1  31 202 K 2.63 427 1  32 — — 1.87 443 1  33 153 DSC 2.69 433 1 118 DSC  34 152 DSC 2.69 433 1  35 220 DSC 3.38 437 1  36 >250  K 2.99 407 1  37 210 K 2.24 389 1  38 215 DSC 3.26 510 1  39 204 DSC 3.01 467 1  40 143 DSC 3.29 431 1  42 154 DSC 2.67 459 1  43 141 DSC 2.67 459 1  44 217 DSC 3.08 473 1  45 138 K 3.15 429 1  46 234 DSC 2.98 433 1  47 215 DSC 2.25 433 1  48 192 DSC 2.67 486 1  49 195 DSC 2.57 488 1  50 247 DSC 2.40 398 1 242 DSC  51 152 K 2.94 494 1  52 281 DSC 2.70 494 1  53 190 DSC 3.24 501 1  54 — — 3.33 457 1  55 204 DSC 2.69 520 1  56 126 DSC 2.69 520 1  57 — — 2.58 493 1  58 — — 3.10 461 1  59 237 DSC 2.89 403 1 234 K  60 — — 2.25 509 1  61 186 DSC 2.93 451 1  62 117 DSC 3.25 473 1  63 193 DSC 2.75 426 1  64 145 DSC 2.92 452 1  65 158 K 2.62 456 1  66 178 K 1.23 440 3  67 — — 2.97 473 1  68 — — 2.76 441 1  69 186 DSC 2.82 447 1  72 224 DSC 3.41 499 1  73 231 DSC 2.25 470 1  74 206 DSC 3.22 454 1  75 — — 3.19 442 1  76 162 (gum) K 2.78 484 1  77 162 (gum) K 2.65 472 1  78 — — 2.64 472 1  80 — — 2.31 472 1  81 318 DSC 2.88 485 1  84 — — 2.26 470 1  85 — — 2.96 440 1  86 206 DSC 3.29 443 1  87 — — 2.37 484 1  88 198 DSC 2.68 524 1  89 301 DSC 2.52 526 1  90 — — 2.22 483 1  91 166 K 2.81 483 1  93 165 DSC 1.97 430 1  96 — — 2.67 517 1  97 — — 5.24 373 5  98 — — 5.43 480 5  99 — — 6.31 450 5 101 >250  K 2.92 407 1 102 >250  K 3.33 441 1 103 >250  K 2.92 407 1 104 >250  K 3.33 441 1 105 284 DSC 3.32 511 1 106 >250  K 2.81 451 1 107 226 DSC 2.88 477 1 108 173 K 2.49 402 1 109 171 K 3.10 494 1 110 116 (gum) K 3.35 428 1 111 220 K 2.46 457 1 112 146 K 2.76 494 1 113  95 (gum) K 3.27 458 1 114  60 (gum) K 2.90 446 1 115 203 K 2.49 430 1 116  95 DSC 2.59 474 1 117 108 DSC 2.89 502 1 118  88 DSC 2.56 486 1 119 106 DSC 3.49 506 1 120 152 DSC 3.06 520 1 121 104 DSC 3.41 536 1 122 182 K 3.06 421 1 124 — — 2.60 424 1 125 270 K 2.85 429 1 126 227 DSC 2.03 374 1 127 333 DSC 2.26 388 1 128 307 DSC 2.04 360 1 129 223 DSC 2.48 404 1 130 — — 2.35 390 1 131 234 DSC 2.05 399 1 132 — — 2.32 422 1 133 — — 2.07 502 1 134 — — 2.40 459 1 135 — — 1.86 459 1 136 231 DSC 2.46 448 1 137 200 DSC 2.56 474 1 138 — — 2.57 474 1 139 — — 2.08 510 1 140 — — 2.64 474 1 141 — — 2.57 518 1 142 — — 2.46 474 1 143 — — 2.79 472 1 144 — — 2.19 475 1 145 182 K 3.06 421 1 146 135 DSC 2.35 486 1 147 >260  K 2.75 473 2 148 154 K 2.66 502 1 149 146 K 2.56 502 2 150 171 DSC 2.40 474 1 151 114 DSC 2.63 502 1 152 140 K 2.63 502 1 153 180 DSC 2.84 490 1 154 185 K 2.84 490 1 155 220 MP50 2.61 504 6 156 245 DSC 2.10 403 1 157 173 DSC 3.19 532 1 158 — — 0.76 405 7 159 179 DSC 2.80 487 1 160 189 DSC 2.50 473 2 161 — DSC 3.37 459 1 162 >260  K 2.43 403 1 163 — DSC 1.96 374 1 164 121 WRS-2A 2.09 470 8 165 — — 4.32 430 9 166 150 K 2.00 499 1 167 263 DSC 2.29 387 1 168 260 DSC 2.83 417 1 169 >260  K 1.98 403 1 170 279 DSC 2.54 398 1 171 — — 2.50 504 6 172 — — 2.25 500 1 173 225 DSC 2.28 457 2 174 199 DSC 2.72 487 2 175 — — 2.72 512 6 176 — — 3.07 526 1 177 115 DSC 2.39 445 2 178 — — 0.84 450 10 179 — — 5.19 490 10 180 143-145 WRS-2A 5.67 490 10 181 — — 4.63 390 11 182 156 K 2.24 456 1 183 209 DSC 3.14 457 1  1i 149 K 2.48 490 1  2i 135 K 2.69 530 1  3i 252 DSC 2.49 506 1  4i 235 DSC 2.30 483 1  5i — — 2.94 457 1  6i 194 DSC 2.47 509 1  7i — — 2.39 502 1  8i >250  K 2.11 375 1  9i 313 DSC 2.41 403 1  10i 192 DSC 2.50 447 1  11i 299 DSC 2.38 494 1  12i 198 DSC 2.49 480 1  13i 306 DSC 2.58 423 1  14i — — 2.72 467 1  15i 295 DSC 2.56 423 1  16i 232 DSC 2.14 529 1  17i 190 K 2.64 508 1  18i 208 DSC 2.57 516 1  19i 148 (gum) K 2.20 515 1  20i 287 DSC 2.46 516 1  21i Decomposition WRS-2A 3.72 526 8   at 250° C.  22i 138 (gum) K 2.57 516 1  23i 136 (gum) K 2.57 516 1  24i 120 (gum) K 3.19 600 2  25i — — 4.33 486 8  26i n.d. 2.27 502 2  27i 197 DSC 3.00 474 1 206 K  28i 235 K 2.92 478 2  29i 129 DSC 2.39 473 2  30i 276 WRS-2A 4.52 404 8  31i >250  K 2.00 449 1 NMR

The NMR experiments were carried out using a Bruker Avance 500 III using internal deuterium lock and equipped with reverse triple-resonance (¹H, ¹³C, ¹⁵N TXI) probe head or using a Bruker Avance DRX 400 spectrometer at ambient temperature, using internal deuterium lock and equipped with reverse double-resonance (¹H, ¹³C, SEI) probe head with z gradients and operating at 400 MHz for the proton and 100 MHz for carbon. Chemical shifts (6) are reported in parts per million (ppm). J values are expressed in Hz.

Compound 3:

¹H NMR (400 MHz, DMSO-d₆): δ 8.78 (d, J=2.0 Hz, 1H), 8.51 (d, J=5.0 Hz, 1H), 8.29 (s, 1H), 8.14 (d, J=1.5 Hz, 1H), 7.99 (d, J=1.0 Hz, 1H), 7.84 (d, J=2.5 Hz, 1H), 7.45-7.50 (m, 2H), 4.99 (t, J=5.3 Hz, 1H), 3.98 (s, 3H), 3.71 (d, J=10.1 Hz, 1H), 3.47 (dd, J=10.6 Hz, 5.6 Hz, 1H), 3.40 (dd, J=10.6 Hz, 5.6 Hz, 1H), 3.32-3.32 (m, 1H, partially obscured by solvent peak), 1.30 (s, 3H).

Compound 4:

¹H NMR (400 MHz, DMSO-d₆): δ 9.00 (s, 1H), 8.43 (d, J=5.0 Hz, 1H), 8.36 (d, J=2.0 Hz, 1H), 8.22 (d, J=2.5 Hz, 1H), 8.08 (d, J=1.5 Hz, 1H), 7.92 (d, J=1.0 Hz, 1H), 7.43 (s, 1H), 7.40 (d, J=5.1 Hz, 1H), 4.98 (t, J=5.3 Hz, 1H), 3.70 (d, J=10.1 Hz, 1H), 3.43 (dd, J=10.6 Hz, 5.1 Hz, 1H), 3.36 (dd, J=10.6 Hz, 5.6 Hz, 1H), 3.29 (d, J=10.6 Hz, 1H, partially obscured by solvent peak), 2.50 (s, 3H, obscured by solvent peak), 1.27 (s, 3H).

Compound 6:

¹H NMR (500 MHz, DMSO-d₆): δ 8.50 (dd, J=7.6 Hz, 1.6 Hz, 1H), 8.43 (d, J=5.4 Hz, 1H), 8.18 (s, 1H), 8.11 (d, J=1.6 Hz, 1H), 7.99 (d, J=1.3 Hz, 1H), 7.83 (dd, J=4.9 Hz, 1.7 Hz, 1H), 7.43 (s, 1H), 7.39 (d, J=5.4 Hz, 1H), 7.01 (dd, J=7.7 Hz, 4.9 Hz, 1H), 5.02 (t, J=5.2 Hz, 1H), 3.95 (s, 3H), 3.68 (d, J=9.8 Hz, 1H), 3.45 (dd, J=10.4 Hz, 5.0 Hz, 1H), 3.39 (dd, J=10.4 Hz, 5.3 Hz, 1H), 3.30 (d, J=9.8 Hz, 1H), 1.29 (s, 3H).

Compound 10:

¹H NMR (500 MHz, DMSO-d₆): δ 8.30 (d, J=5.4 Hz, 1H), 8.11 (s, 1H), 8.04 (s, 1H), 7.98 (br s, 1H), 7.91 (s, 1H), 7.38 (s, 1H), 7.23 (d, J=5.4 Hz, 1H), 6.18 (t, J=5.0 Hz, 1H), 4.99 (t, J=4.9 Hz, 1H), 3.85 (s, 3H), 3.69 (d, J=9.8 Hz, 1H), 3.49-3.60 (m, 4H), 3.44 (dd, J=10.4 Hz, 4.7 Hz, 1H), 3.34-3.38 (m, 1H, partially obscured by solvent peak), 3.25-3.32 (m, 4H), 1.27 (s, 3H).

Compound 103:

¹H NMR (500 MHz, DMSO-d₆): δ 8.52 (d, J=3.8 Hz, 1H), 8.33-8.41 (m, 2H), 7.94 (s, 1H), 7.89 (s, 1H), 7.84 (d, J=4.1 Hz, 1H), 7.59 (s, 1H), 7.00 (dd, J=7.4 Hz, 5.2 Hz, 1H), 5.05 (t, J=5.2 Hz, 1H), 3.94 (s, 3H), 3.67 (d, J=9.8 Hz, 1H), 3.41-3.47 (m, 1H), 3.35-3.39 (m, 1H, partially obscured by solvent peak), 3.34-3.38 (m, 1H, partially obscured by solvent peak), 1.27 (s, 3H).

Compound 33:

¹H NMR (500 MHz, DMSO-d₆): δ 8.55 (dd, J=7.9 Hz, 1.6 Hz, 1H), 8.45 (d, J=5.4 Hz, 1H), 8.10 (d, J=1.6 Hz, 1H), 8.07 (s, 1H), 7.98 (d, J=1.3 Hz, 1H), 7.80 (dd, J=4.7 Hz, 1.6 Hz, 1H), 7.44 (s, 1H), 7.41 (d, J=5.7 Hz, 1H), 7.02 (dd, J=7.7 Hz, 4.9 Hz, 1H), 5.03 (t, J=5.4 Hz, 1H), 4.49 (t, J=4.7 Hz, 2H), 3.72 (t, J=4.7 Hz, 2H), 3.67 (d, J=9.8 Hz, 1H), 3.44 (dd, J=10.7 Hz, 5.3 Hz, 1H), 3.39 (dd, J=10.4 Hz, 5.3 Hz, 1H), 3.29-3.32 (m, 4H), 1.29 (s, 3H).

Compound 115:

¹H NMR (500 MHz, DMSO-d₆): δ 8.51 (d, J=7.6 Hz, 1H), 8.45 (d, J=5.4 Hz, 1H), 8.20 (s, 1H), 8.13 (s, 1H), 8.02 (s, 1H), 7.97 (t, J=6.1 Hz, 1H), 7.82 (dd, J=4.7 Hz, 1.2 Hz, 1H), 7.46 (s, 1H), 7.41 (d, J=5.4 Hz, 1H), 7.03 (dd, J=7.9 Hz, 5.0 Hz, 1H), 3.96 (s, 3H), 3.64 (d, J=10.1 Hz, 1H), 3.34 (dd, J=13.6 Hz, 6.9 Hz, 1H), 3.28 (d, J=10.1 Hz, 1H), 3.21 (dd, J=13.6, 5.6 Hz, 1H), 1.81 (s, 3H), 1.28 (s, 3H).

Compound 50:

¹H NMR (500 MHz, DMSO-d₆): δ 9.16 (s, 1H), 8.61 (s, 2H), 8.43 (d, J=5.4 Hz, 1H), 8.08 (d, J=1.9 Hz, 1H), 7.92 (d, J=1.6 Hz, 1H), 7.44 (s, 1H), 7.42 (d, J=5.4 Hz, 1H), 4.98 (t, J=5.4 Hz, 1H), 3.69 (d, J=9.5 Hz, 1H), 3.44 (dd, J=10.7 Hz, 5.3 Hz, 1H), 3.34-3.39 (m, 1H, partially obscured by solvent peak), 3.29 (d, J=9.5 Hz, 1H), 2.60 (s, 3H), 1.27 (s, 3H).

Compound 59:

¹H NMR (500 MHz, DMSO-d₆): δ 8.43-8.48 (m, 2H), 8.12 (s, 1H), 8.06 (s, 1H), 7.99 (s, 1H), 7.63 (s, 1H), 7.45 (s, 1H), 7.40 (d, J=5.4 Hz, 1H), 5.02 (br s, 1H), 3.92 (s, 3H), 3.68 (d, J=10.1 Hz, 1H), 3.43-3.48 (m, 1H), 3.36-3.39 (m, 1H), 3.33-3.38 (m, 1H, partially obscured by solvent peak), 2.28 (s, 3H), 1.29 (s, 3H).

Compound 65:

¹H NMR (500 MHz, DMSO-d₆): δ 9.15 (s, 1H), 8.68 (d, J=1.9 Hz, 1H), 8.58 (d, J=1.9 Hz, 1H), 8.41 (d, J=5.7 Hz, 1H), 8.07 (d, J=1.9 Hz, 1H), 7.91 (d, J=1.6 Hz, 1H), 7.43 (s, 1H), 7.40 (d, J=5.4 Hz, 1H), 4.97 (t, J=5.4 Hz, 1H), 3.69 (d, J=9.8 Hz, 1H), 3.44 (dd, J=10.7 Hz, 5.3 Hz, 1H), 3.33-3.38 (m, 3H, partially obscured by solvent peak), 3.29 (d, J=9.5 Hz, 1H), 3.20 (s, 3H), 2.97 (t, J=7.4 Hz, 2H), 1.93 (q, J=6.6 Hz, 2H) 1.27 (s, 3H).

Compound 93:

¹H NMR (400 MHz, DMSO-d₆): δ 8.98 (s, 1H), 8.64 (s, 1H), 8.49-8.58 (m, 2H), 8.39 (d, J=5.6 Hz, 1H), 8.04 (s, 1H), 7.90 (s, 1H), 7.32-7.38 (m, 2H), 4.91 (t, J=5.3 Hz, 1H), 3.70 (d, J=10.1 Hz, 1H), 3.42 (dd, J=13.2 Hz, 6.3 Hz, 1H), 3.33-3.37 (m, 1H, partially obscured by solvent peak), 3.20-3.32 (m, 1H, partially obscured by solvent peak), 2.80 (d, J=4.0 Hz, 3H), 2.52 (s, 3H), 1.24 (s, 3H).

Compound 124:

¹H NMR (500 MHz, DMSO-d₆): δ 8.97 (s, 1H), 8.63 (br s, 2H), 8.21 (s, 1H), 8.01 (s, 1H), 7.65 (d, J=4.4 Hz, 1H), 7.57 (s, 1H), 5.02 (br s, 1H), 4.13 (s, 3H), 3.72 (d, J=9.5 Hz, 1H), 3.30-3.47 (m, 3H, partially obscured by solvent peak), 1.31 (s, 3H).

Compound 140:

¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.92 (s, 1H) 8.55 (s, 1H) 8.39 (d, J=5.4 Hz, 1H) 8.07 (d, J=1.3 Hz, 1H) 7.92 (s, 1H) 7.42 (s, 1H) 7.35 (d, J=5.4 Hz, 1H) 5.00 (t, J=5.4 Hz, 1H) 3.89-4.01 (m, 5H) 3.69 (d, J=9.8 Hz, 1H) 3.40-3.54 (m, 3H) 3.35-3.40 (m, 1H) 3.30 (d, J=9.8 Hz, 1H) 2.89-3.05 (m, 1H) 1.78-1.95 (m, 4H) 1.27 (s, 3H).

Compound 4i:

¹H NMR (400 MHz, DMSO-d₆): δ 8.49 (d, J=5.6 Hz, 1H), 8.36 (d, J=2.0 Hz, 1H), 8.21 (s, 1H), 8.12 (d, J=1.5 Hz, 1H), 8.02 (d, J=1.5 Hz, 1H), 7.43-7.46 (m, 2H), 7.14 (s, 1H), 7.11 (s, 1H), 6.81 (d, J=1.0 Hz, 1H), 5.21 (s, 2H), 5.00 (t, J=5.6 Hz, 1H), 3.73 (s, 3H), 3.69 (d, J=10.1 Hz, 1H), 3.46 (dd, J=10.6 Hz, J=5.6 Hz, 1H), 3.39 (dd, J=10.6 Hz, J=5.6 Hz, 1H), 3.37-3.44 (m, 1H, partially obscured by solvent peak), 2.14 (s, 3H), 1.30 (s, 3H).

Compound 7i:

¹H NMR (400 MHz, DMSO-d₆): δ 8.49 (d, J=5.0 Hz, 1H), 8.36 (d, J=2.2 Hz, 1H), 8.23 (s, 1H), 8.13 (d, J=2.2 Hz, 1H), 8.03 (d, J=1.6 Hz, 1H), 7.41-7.48 (m, 2H), 7.13 (s, 1H), 5.00 (t, J=5.3 Hz, 1H), 4.03-4.11 (m, 2H), 3.69 (d, J=10.1 Hz, 1H), 3.55 (t, J=4.4 Hz, 4H), 3.47 (dd, J=10.6 Hz, J=5.0 Hz, 1H) 3.40 (dd, J=10.6 Hz, J=5.0 Hz, 1H), 3.37-3.44 (m, 1H, partially obscured by solvent peak), 2.60 (t, J=6.5 Hz, 2H), 2.41-2.48 (m, 4H), 2.14 (s, 3H), 1.31 (s, 3H).

Compound 13i:

¹H NMR (400 MHz, DMSO-d₆): δ 8.54 (d, J=5.6 Hz, 1H), 8.51 (d, J=2.5 Hz, 1H), 8.28 (s, 1H), 8.13 (s, 1H), 8.00 (s, 1H), 7.62 (d, J=2.5 Hz, 1H), 7.51 (d, J=5.6 Hz, 1H), 7.48 (s, 1H), 4.98 (t, J=5.3 Hz, 1H), 3.72 (d, J=10.1 Hz, 1H), 3.55 (s, 3H), 3.45 (dd, J=10.6 Hz, J=5.6 Hz, 1H) 3.40 (dd, J=10.6 Hz, J=5.6 Hz, 1H), 3.33-3.38 (m, 1H, partially obscured by solvent peak), 1.31 (s, 3H).

OR

Optical Rotation is measured with a polarimeter such as e.g. 341 Perkin Elmer, an Autopol IV automatic polarimeter (Rodolph research analytical) or a P-2000 (Jasco). [α]^(θ) _(λ)=(100*α)/(c*1)  Specific rotation (OR):

α (measured rotation) is the angle through which plane polarized light is rotated by a solution of mass concentration c and path length 1. Concentration is in grams per 100 mL; path length 1 is in decimeters and is 1.000 decimeter.

θ is the temperature (° C.) and λ the wavelength of the light used.

Unless otherwise indicated, temperature is 20° C., and the sodium D line is used (589 nanometer).

Concentration N^(o) OR (°) (g/100 mL)  6 +19.53 0.292  7 −20.03 0.314  11 −26.6 0.222  14 +34.19 0.31  19 +18.92 0.227  20 +13.64 0.22  21 +34 0.25  22 +28.4 0.25  23 +16.15 0.26  24 +12 0.25  25 +35.17 0.29  26 −5.19 0.27  27 +33.67 0.3  28 +35.38 0.26  29 +16.72 0.227  30 +35.44 0.245  33 +18.65 0.252  34 −17.22 0.331  35 +32.53 0.289  36 +22 0.25  37 +21.86 0.247  38 +27.72 0.227  39 +33.52 0.254  42 +29.63 0.27  43 +47.6 0.25  44 +18.45 0.206  45 +15.47 0.278  46 +6.27 0.239  47 +11.6 0.25  48 +21.88 0.288  49 +14.9 0.255  50 +38.97 0.29  51 +13.6 0.25  52 +25.91 0.22  53 +8.42 0.285  54 +10.31 0.291  55 +9.6 0.25  56 +43.33 0.3  57 +9.63 0.27  58 +18.08 0.26  59 +20.48 0.293  60 +5.93 0.27  61 +17.27 0.249  62 +20.77 0.284  63 +40.39 0.255  64 +30.74 0.244  65 +24.71 0.263  66 +36.12 0.263  67 +16.96 0.283  68 +12.93 0.224  69 +19.86 0.252  72 +13.96 0.251  73 +20.87 0.288  74 +53.77 0.208  75 +46.8 0.25  76 +42.31 0.26  77 +57.87 0.233  78 +37.69 0.26  80 +10.87 0.23  81 +16.94 0.213  86 +16.8 0.25  87 +11.54 0.39  88 +17.18 0.39  89 +11.76 0.34  90 +16.77 0.31  91 +24.33 0.3  93 +16.67 0.258  96 +13.33 0.33 103 +18.72 0.262 104 +9.2 0.25 109 −50.55 0.275 122 +39.16 0.227 129 +25.54 0.255 132 +8.4 0.25 133 +13.64 0.33 134 +11 0.227 135 +12.96 0.27 136 +21.59 0.245 137 +8.01 0.237 138 +31.25 0.256 139 +18 0.25 140 +19.67 0.3 141 +18.93 0.28 142 +16.98 0.265 143 +26.07 0.28 144 +14.29 0.28 145 +39.16 0.227 146 +14.29 0.28 147 +18.64 0.279 148 +38.46 0.26 149 −8.76 0.251 150 +19.16 0.308 151 +20.23 0.262 152 +14.7 0.279 153 +41.42 0.268 154 −6.45 0.248 156 +16.54 0.254 157 +18 0.25 159 +13.39 0.254 160 +15.2 0.25 161 +11.59 0.276 163 +11.88 0.227 164 +5.55 0.108 (MeOH) 165 +94.67 0.072 (MeOH) 167 +13.01 0.269 168 +8.09 0.346 169 +24.92 0.301 170 +55.71 0.28 173 +4.62 0.26 174 +14.71 0.272 176 +15.83 0.24 177 +9.57 0.282 181 +3.53 0.17 (MeOH, 26.6° C.) 182 +17.52 0.274  1i +21.89 0.37  2i +20.37 0.324  3i +22.86 0.28  4i +16.95 0.218  5i +22.63 0.234  6i +13.05 0.237  7i +19.42 0.232  8i +14.81 0.27  9i +17.92 0.24  10i +13.08 0.26  11i +32 0.25  12i +25 0.28  13i +39.62 0.26  14i +30.35 0.264  16i +20 0.265  17i +16.98 0.265  19i +16.67 0.27  20i +13.96 0.265  22i +38.52 0.27  23i −12.5 0.28  24i +45.19 0.27  26i +20.63 0.286  29i +22.9 0.262  30i +6.50 0.123 (24.4° C.) OR data: Solvent: DMF (unless otherwise indicated); temperature: 20° C. (unless otherwise indicated); wavelength: 589 nm; ‘Conc.’ means concentration of the sample in grams per 100 mL; ‘OR’ means optical rotation (specific rotation); ‘Co. No.’ means compound number SFC-MS Method

The SFC measurement was performed using an Analytical Supercritical fluid chromatography (SFC) system composed by a binary pump for delivering carbon dioxide (CO₂) and modifier, an autosampler, a column oven, a diode array detector equipped with a high-pressure flow cell standing up to 400 bars. If configured with a Mass Spectrometer (MS) the flow from the column was brought to the (MS). It is within the knowledge of the skilled person to set the tune parameters (e.g. scanning range, dwell time . . . ) in order to obtain ions allowing the identification of the compound's nominal monoisotopic molecular weight (MW). Data acquisition was performed with appropriate software.

TABLE Analytical SFC-MS Methods (flow expressed in mL/min; column temperature (T) expressed in ° C.; run time expressed in minutes, backpressure (BPR) expressed in bars) Flow Run time Method column mobile phase gradient Col T BPR Method 1 Chiralpak ® A: CO₂ 30% B hold 3.5 3 AS-3 column B: iPrOH 3 min, 35 103 (3 μm, 100 × (0.3% 4.6 mm) iPrNH₂)

TABLE Analytical SFC data (R_(t) means retention time (in minutes), [M + H]⁺ means the protonated mass of the compound, method refers to the method used for SFC-MS analysis of enantiomerically pure compounds). Compound number Rt [M + H]⁺ Chiral purity UV Area % Method 55 1.29 520 100.00 1 56 1.77 520 100.00 1 Pharmacological Part Biological assay A Inhibition of auto-phosphorylation of recombinant human NF-kappaB-inducing Kinase (NIK/MAP3K14) Activity (AlphaScreen®)

NIK/MAP3K14 auto-phosphorylation activity was measured using the AlphaScreen® (αscreen) format (Perkin Elmer). All compounds tested were dissolved in dimethyl sulfoxide (DMSO) and further dilutions were made in assay buffer. Final DMSO concentration was 1% (v/v) in assays. Assay buffer was 50 mM Tris pH 7.5 containing 1 mM EGTA (ethylene glycol tetraacetic acid), 1 mM DTT (dithiothreitol), 0.1 mM Na₃VO₄, 5 mM MgCl₂, 0.01% Tween® 20. Assays were carried out in 384 well Alphaplates (Perkin Elmer). Incubations consisted of compound, 25 microM Adenosine-5′-triphosphate (ATP), and 0.2 nM NIK/MAP3K14. Incubations were initiated by addition of GST-tagged NIK/MAP3K14 enzyme, carried out for 1 h at 25° C. and terminated by addition of stop buffer containing anti-phospho-IKK Ser176/180 antibody. Protein A Acceptor and Glutathione-Donor beads were added before reading using an EnVision® Multilabel Plate Reader (Perkin Elmer). Signal obtained in the wells containing blank samples was subtracted from all other wells and IC₅₀'s were determined by fitting a sigmoidal curve to % inhibition of control versus Log₁₀ compound concentration.

Biological Assay B

Effect of Compounds on P-IKKα Levels in L363 (NIK Translocated Multiple Myeloma) Cells

All compounds tested were dissolved in DMSO and further dilutions were made in culture medium. Final DMSO concentration was 1% (v/v) in cell assays. The human L363 cells (ATCC) were cultured in RPMI 1640 medium supplemented with GlutaMax and 10% fetal calf serum (PAA). Cells were routinely maintained at densities of 0.2×10⁶ cells per ml-1×10⁶ cells per ml at 37° C. in a humidified 5% CO₂ atmosphere. Cells were passaged twice a week splitting back to obtain the low density. Cells were seeded in 96 well plates (Nunc 167008) at 2×10⁶ per ml media in a volume of 75 μl per well plus 25 μl 1 μg/ml recombinant human B-cell activating factor (BAFF/BLyS/TNFSF13B). Seeded cells were incubated at 37° C. in a humidified 5% CO₂ atmosphere for 24 hr. Drugs and/or solvents were added (20 μl) to a final volume of 120 μl. Following 2 hr treatment plates were removed from the incubator and cell lysis was achieved by the addition of 30 μl 5× lysis buffer followed by shaking on a plate shaker at 4° C. for 10 min. At the end of this incubation lysed cells were centrifuged at 800×g for 20 min at 4° C. and the lysate was assessed for P-IKK levels by sandwich immuno-assay carried out in anti-rabbit antibody coated Mesoscale plates. Within an experiment, the results for each treatment were the mean of 2 replicate wells. For initial screening purposes, compounds were tested using an 8 point dilution curve (serial 1:3 dilutions). For each experiment, controls (containing MG132 and BAFF but no test drug) and a blank incubation (containing MG132 and BAFF and 10 μM ADS 125117, a test concentration known to give full inhibition) were run in parallel. The blank incubation value was subtracted from all control and sample values. To determine the IC₅₀ a sigmoidal curve was fitted to the plot of % inhibition of control P-IKKα levels versus Log₁₀ compound concentration.

Biological Assay C

Determination of Antiproliferative Activity on JJN-3 (NIK Translocated) and KMS12-BM (NIK WT) Multiple Myeloma Cells

All compounds tested were dissolved in DMSO and further dilutions were made in culture medium. Final DMSO concentration was 0.3% (v/v) in cell proliferation assays. Viability was assessed using CellTiter-Glo cell viability assay kit (Promega). The human JJN-3 and KMS12-BM cells (DSMZ) were cultured in RPMI 1640 medium supplemented with 2 mM L-glutamine, and 10% fetal calf serum (PAA). Cells were routinely kept as suspension cells at 37° C. in a humidified 5% CO₂ atmosphere. Cells were passaged at a seeding density of 0.2×10⁶/ml twice a week. Cells were seeded in black tissue culture treated 96-well plates (Perkin Elmer). Densities used for plating ranged from 15000 (JJN3) to 20000 (KMS12BM) cells per well in a total volume of 135 μl medium. Drugs and/or solvents were added (15 μl) to a final volume of 150 μl. Following 96 hr of treatment, plates were removed from the incubator and allowed to equilibrate to room temperature for approx 10 min. 75 μl CellTiter-Glo reagent was added to each well that was then covered (Perkin Elmer Topseal) and shaken on plate shaker for 10 min. Luminescence was measured on a HTS Topcount (Perkin Elmer). Within an experiment, the results for each treatment were the mean of 2 replicate wells. For initial screening purposes, compounds were tested using a 9 point dilution curve (serial 1:3 dilutions). For each experiment, controls (containing no drug) and a blank incubation (containing cells read at the time of compound addition) were run in parallel. The blank value was subtracted from all control and sample values. For each sample, the mean value for cell growth (in relative light units) was expressed as a percentage of the mean value for cell growth of the control.

Data for the compounds of the invention in the above assays are provided in Table A (the values in Table are averaged values over all measurements on all batches of a compound; ‘n.c.’ means not calculated)

TABLE A Auto- Inhibition phosphorylation of KMS-12 JJN-3 inhibition of pIKKα_L- Proliferation Proliferation Com- NIK 363 inhibition inhibition pound (IC50 (nM)) (IC50 (nM)) (IC50 (nM)) (IC50 (nM))  1 n.c. 81.3 ~2692 79  2 13.2 21.4 >10000 74  3 8.3 n.c. >10000 81  4 3.6 n.c. ~7413 97  5 ~8.51 n.c. >10000 170  6 2.4 n.c. >10000 ~245  7 15.5 n.c. >10000 1585  9 5.3 n.c. 427 219  10 8.5 n.c. >10000 58  11 10.5 n.c. >10000 ~347  12 12.9 n.c. >10000 589  13 28.8 n.c. >10000 447  14 5.5 n.c. >10000 372  15 2.9 n.c. >10000 24  16 3.8 n.c. >10000 245  17 2.5 n.c. >10000 288  18 9.1 n.c. >10000 776  19 14.5 n.c. >10000 912  20 0.9 n.c. >10000 1585  21 22.4 n.c. >10000 813  22 10.2 n.c. >10000 417  23 4.9 n.c. 7413 708  24 123.0 n.c. >10000 6918  25 6.2 n.c. >10000 1479  26 4.1 n.c. >10000 794  27 3.6 n.c. 7413 1514  28 3.2 n.c. 3090 813  29 6.6 n.c. 7244 1549  30 51.3 n.c. >10000 1259  31 9.8 n.c. >10000 1995  32 6.5 n.c. 437 89  33 4.2 n.c. >10000 298  34 38.0 n.c. >10000 2884  35 15.9 n.c. >10000 794  36 3.3 n.c. >10000 288  37 1.8 n.c. >10000 3467  38 19.5 n.c. >10000 79  39 8.5 n.c. >10000 324  40 16.6 n.c. 3802 550  42 6.2 n.c. >10000 347  43 4.0 n.c. >10000 115  44 9.3 n.c. >10000 81  45 9.1 n.c. >10000 195  46 3.0 4.7 ~7943 28  47 13.2 n.c. >10000 1122  48 2.9 1.2 >10000 ~295  49 1.6 0.8 ~9333 35  50 1.3 4.2 6607 145  51 3.0 2.8 >10000 31  52 ~1.48 0.7 871 251  53 95.5 n.c. >10000 3467  54 39.8 n.c. >10000 4074  55 3.8 67.6 1349 69  56 3.5 ~7244 ~148 7  57 4.3 13.8 ~8128 316  58 6.9 ~17 >10000 200  59 2.5 13.2 >10000 16  60 7.2 70.8 >10000 708  61 3.0 19.5 >10000 389  62 29.5 n.c. >10000 977  63 2.9 17.4 >10000 98  64 4.7 27.5 6457 35  65 4.5 15.5 >10000 263  66 3.3 ~141 >10000 41  67 12.3 186.2 >10000 204  68 3.9 ~20 5129 98  69 3.2 ~129 >10000 263  72 25.1 66.1 >10000 1047  73 1.6 ~13 ~234 144  74 16.2 ~120 >10000 141  75 9.8 18.2 >10000 >10000  76 5.1 26.9 >10000 >10000  77 5.0 25.7 >10000 60  78 4.7 28.2 >10000 589  80 3.7 38.9 >10000 525  81 4.7 20.9 >10000 513  84 5.6 11.8 >10000 4677  85 2.5 3.0 >10000 372  86 12.0 53.7 >10000 1175  87 3.8 27.5 >10000 427  88 4.2 22.4 >10000 148  89 3.6 14.8 >10000 912  90 1.9 32.4 >10000 5888  91 8.9 5.4 >10000 81  93 2.1 5.6 9550 1445  96 2.2 1.1 >10000 65  97 9.8 42.7 >10000 1820  98 50.1 45.7 >10000 832  99 123.0 275.4 >10000 708 101 2.2 n.c. 2455 204 102 6.5 n.c. >10000 1585 103 1.0 n.c. 1585 120 104 11.2 n.c. >10000 112 105 30.9 n.c. ~3715 2239 106 3.4 n.c. 2630 275 107 4.8 n.c. 562 309 108 25.1 n.c. ~3981 2138 109 38.0 n.c. >10000 794 110 33.9 n.c. >10000 1862 111 14.8 n.c. 3163 669 112 22.9 n.c. >10000 1820 113 34.7 n.c. >10000 5754 114 32.4 n.c. >10000 3548 115 10.0 n.c. 6310 741 116 85.1 n.c. >10000 2042 117 45.7 n.c. >10000 >10000 118 64.6 n.c. 4074 4571 119 128.8 n.c. 1995 1288 120 79.4 n.c. 1230 631 121 117.5 n.c. 2512 1413 122 9.5 n.c. 4786 478 124 3.8 n.c. >10000 ~144 125 9.8 n.c. 891 166 126 147.9 n.c. >10000 2512 127 4.5 n.c. >10000 ~7079 128 6.3 n.c. ~194.98 209 129 1.8 n.c. >10000 562 130 4.6 n.c. >10000 468 131 10.2 n.c. 4266 1318 132 12.9 n.c. >10000 3311 133 22.9 n.c. >10000 ~1949 134 38.9 n.c. >10000 >10000 135 n.c. n.c. n.c. n.c. 136 18.2 n.c. >10000 1995 137 16.2 n.c. >10000 525 138 29.5 n.c. >10000 1514 139 17.8 n.c. >10000 ~10000 140 4.8 12.0 >10000 427 141 18.6 354.8 4786 741 142 15.1 n.c. >10000 6310 143 7.8 n.c. >10000 347 144 24.0 n.c. >10000 >10000 145 9.5 n.c. 4786 479 146 2.8 4.1 7079 5.2 147 7.9 n.c. n.c. n.c. 148 8.5 13.8 >10000 135 149 8.9 7.8 >10000 29 150 12.0 25.7 >10000 132 151 5.5 13.8 >10000 66 152 14.1 85.1 n.c. n.c. 153 5.8 9.3 ~5888 240 154 7.2 3.0 ~7943 148 155 12.0 19.5 ~2884 81 156 2.3 6.3 ~6457 105 157 9.3 25.7 >10000 62 158 1.6 2.3 >10000 49 159 5.6 5.9 >10000 89 160 3.9 2.1 >10000 115 161 28.2 46.8 >10000 417 162 3.0 1.3 >10000 60 163 34.7 n.c. ~5012 3162 164 102.3 1175 1660 1175 165 1.3 6.2 >10000 117 166 25.7 229.0 n.c. n.c. 167 1.7 2.8 >10000 30 168 3.0 2.4 >10000 39 169 2.7 9.9 4898 263 170 1.1 1.0 >10000 5 171 7.4 6.9 >10000 12 172 4.1 3.9 ~2188 26 173 15.1 69.2 >10000 933 174 6.5 4.0 n.c. n.c. 175 19.5 n.c. n.c. n.c. 176 4.8 n.c. n.c. n.c. 177 5.5 21.4 >10000 205 178 18.2 51.3 n.c. n.c. 179 93.3 1445 n.c. n.c. 180 338.8 616.6 n.c. n.c. 181 5.2 25.1 n.c. n.c. 182 15.1 109.6 >10000 49 183 15.8 40.7 >10000 63  1i 1.1 2.6 3890 347  2i 1.8 1.1 5495 479  3i 1.3 3.3 >10000 ~1778  4i 1.3 8.9 >10000 316  5i 4.5 15.8 5012 282  6i 1.0 10.0 5129 275  7i 1.2 3.7 9550 115  8i 4.5 74.1 >10000 776  9i 1.0 8.5 >10000 120  10i 3.0 n.c. 4786 339  11i 1.9 3.2 >10000 ~1122  12i 1.1 0.9 813 18  13i 1.9 0.9 >10000 31  14i 1.4 n.c. >10000 24  15i 3.6 n.c. >10000 ~427  16i 1.2 11.0 >10000 25  17i 1.9 1.8 >10000 33  18i 0.9 4.9 >10000 49  19i 0.6 2.5 >10000 25  20i 2.3 1.5 >10000 41  21i 64.6 550 n.c. n.c.  22i 3.4 2.1 9120 33  23i 2.3 2.9 >10000 30  24i 23.4 5.5 >10000 32  25i 1.7 9.5 >10000 120  26i 2.1 2.3 >10000 28  27i 5.8 13.8 >10000 148  28i 7.6 21.4 n.c. n.c.  29i 3.0 3.7 >10000 100  30i 4.6 14.5 n.c. n.c.  31i 3.3 n.c. >10000 ~5012 Prophetic Composition Examples

“Active ingredient” (a.i.) as used throughout these examples relates to a compound of Formula (I), including any tautomer or stereoisomeric form thereof, or a pharmaceutically acceptable addition salt, or a solvate thereof; in particular to any one of the exemplified compounds.

Typical examples of recipes for the formulation of the invention are as follows:

1. Tablets

Active ingredient 5 to 50 mg Di-calcium phosphate 20 mg Lactose 30 mg Talcum 10 mg Magnesium stearate 5 mg Potato starch ad 200 mg 2. Suspension

An aqueous suspension is prepared for oral administration so that each milliliter contains 1 to 5 mg of active ingredient, 50 mg of sodium carboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg of sorbitol and water ad 1 ml.

3. Injectable

A parenteral composition is prepared by stirring 1.5% (weight/volume) of active ingredient in 0.9% NaCl solution or in 10% by volume propylene glycol in water.

4. Ointment

Active ingredient 5 to 1000 mg Stearyl alcohol 3 g Lanoline 5 g White petroleum 15 g Water ad 100 g

In this Example, active ingredient can be replaced with the same amount of any of the compounds according to the present invention, in particular by the same amount of any of the exemplified compounds. 

What is claimed is:
 1. A compound of Formula (I):

a tautomer or a stereoisomeric form thereof, wherein R¹ represents C₁₋₄alkyl; R² represents C₁₋₆alkyl, or C₁₋₆alkyl substituted with one R⁵; Y represents CR⁴ or N; R⁴ represents hydrogen or halo; R⁵ represents Het^(3a), —NR^(6a)R^(6b), or —OR⁷; R^(6a) represents or C₁₋₄alkyl; R^(6b) represents C₁₋₄alkyl; C₃₋₆cycloalkyl; —C(═O)—C₁₋₄alkyl; or C₁₋₄alkyl substituted with one substituent selected from the group consisting of —OH and —S(═O)₂—C₁₋₄alkyl; R⁷ represents hydrogen, C₁₋₄alkyl, —C₁₋₄alkyl-NR^(8a)R^(8b), —C(═O)—R⁹, or —C₁₋₄alkyl-Het^(3b); R^(8a) represents hydrogen; R^(8b) represents C₁₋₄alkyl, or C₃₋₆cycloalkyl; R⁹ represents C₁₋₆alkyl, or C₁₋₆alkyl substituted with one; R³ represents a 6-membered heteroaromatic ring containing 1 or 2 N-atoms, optionally substituted with one, two or three substituents each independently selected from the group consisting of halo; cyano; C₁₋₆alkyl; —O—C₁₋₄alkyl; —C(═O)—R¹⁰; —O—C₁₋₄alkyl-R¹²; C₃₋₆cycloalkyl; —O—C₃₋₆cycloalkyl; Het^(1a); —O-Het^(1b); R¹⁸; R²¹; —P(═O)—(C₁₋₄alkyl)₂; —NR^(17a)R^(17b); C₁₋₄alkyl substituted with one, two or three halo atoms; C₁₋₄alkyl substituted with one, two or three —OH substituents; C₁₋₄alkyl substituted with one R¹³; C₂₋₆alkenyl; and C₂₋₆alkenyl substituted with one R¹³; or R³ represents 2-oxo-1,2-dihydropyridin-3-yl, wherein said 2-oxo-1,2-dihydropyridin-3-yl may optionally be substituted on the N-atom with a substituent selected from the group consisting of C₁₋₆alkyl; C₁₋₄alkyl substituted with one, two or three —OH substituents; C₁₋₄alkyl substituted with one R¹³; C₁₋₄alkyl substituted with one R¹⁸; and wherein said 2-oxo-1,2-dihydropyridin-3-yl may optionally be substituted on the ring carbon atoms with in total one, two or three substituents each independently selected from the group consisting of halo; C₁₋₆alkyl; —C(═O)—R¹⁰; R¹⁰ represents —O—C₁₋₄alkyl, —NR^(11a)R^(11b) or Het²; R¹⁸ represents a 5-membered aromatic ring containing one, two or three N-atoms; wherein said 5-membered aromatic ring may optionally be substituted with one substituent selected from the group consisting of C₁₋₄alkyl and C₃₋₆cycloalkyl; R²¹ represents 3,6-dihydro-2H-pyran-4-yl; Het^(1a), Het^(1c) and Het^(1d) each independently is selected from the group consisting of

optionally substituted, on one N-atom with a substituent selected from the group consisting of C₁₋₄alkyl, C₃₋₆cycloalkyl, and C₁₋₄alkyl substituted with one —OH; and optionally substituted on one, two or three ring C-atoms with one or two substituents each independently selected from the group consisting of halo, and C₁₋₄alkyl; Het^(1b) is selected from

optionally substituted, on one or two ring N-atoms with a substituent each independently selected from the group consisting of C₁₋₄alkyl, and C₃₋₆cycloalkyl; and optionally substituted on one, two or three ring C-atoms with one or two halo substituents; Het² represents a heterocyclyl of formula (b-1):

(b-1) represents a N-linked 4- to 7-membered monocyclic saturated heterocyclyl optionally containing one additional N-atom; wherein in case (b-1) contains one additional N-atom, said one N-atom may optionally be substituted with C₁₋₄alkyl; and wherein (b-1) may optionally be substituted on one, two or three ring C-atoms with one or two —OH substituents; R^(11b) represents C₁₋₄alkyl; R¹³ represents —O—C₁₋₄alkyl, —C(═O)NR^(15a)R^(15b), —NR^(19a)R^(19b), C₃₋₆cycloalkyl, or Het^(1d); R¹² represents —OH, —O—C₁₋₄alkyl, —C(═O)NR^(14c)R^(14d), C₃₋₆cycloalkyl, or Het^(1c); Het^(3a), and Het^(3b) each independently represents a heterocyclyl of formula (c-1):

(c-1) represents a N-linked 4- to 7-membered monocyclic saturated heterocyclyl optionally containing one additional heteroatom selected from O and N; R^(11a), R^(14a), R^(14c), R^(15a), R^(17a) and R^(19a) each independently represents hydrogen or C₁₋₄alkyl; R^(14d), R^(15b), R^(17b) and R^(19b) each independently represents C₁₋₄alkyl; C₃₋₆cycloalkyl; C₁₋₄alkyl substituted with one —O—C₁₋₄alkyl substituent; or a pharmaceutically acceptable addition salt, or a solvate thereof.
 2. The compound according to claim 1, wherein R¹ represents methyl; R² represents methyl or —CH₂—OH.
 3. The compound according to claim 1, wherein R⁴ is hydrogen.
 4. The compound according to claim 1, wherein R⁵ represents —OR⁷; and R⁷ represents hydrogen.
 5. A compound selected from:

tautomers and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvates thereof.
 6. A pharmaceutical composition comprising a compound of claim 1 or claim 5 and a pharmaceutically acceptable carrier or diluent.
 7. A method of treating a B-cell malignancy selected from multiple myeloma, Hodgkin's lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma and chronic lymphocytic leukemia in a warm-blooded animal which comprises administering to said animal an effective amount of a compound of claim
 1. 8. The method of claim 7, wherein the B-cell malignancy is multiple myeloma. 